Novel compounds

ABSTRACT

Compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     are useful as inhibitors of human neutrophil elastase.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.11181201.2 filed on Sep. 14, 2011, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to heterocyclic compounds, which arepyrimidine derivatives having human neutrophil elastase inhibitoryproperties, and their use in therapy.

2. Discussion of the Background

Human neutrophil elastase (HNE) is a 32 kDa serine proteinase found inthe azurophilic granules of neutrophils. It has a role in thedegradation of a wide range of extracellular matrix proteins, includingfibronectin, laminin, proteoglycans, Type III and Type IV collagens aswell as elastin (see Bieth, G. In Regulation of Matrix accumulation,Mecham, R. P. (Eds), Academic Press, NY, USA 1986, 217-306, which isincorporated herein by reference in its entirety). HNE has long beenconsidered to play an important role in homeostasis through repair anddisposal of damaged tissues via degradation of the tissue structuralproteins. It is also relevant in the defense against bacterial invasionby means of degradation of the bacterial body. In addition to itseffects on matrix tissues, HNE has been implicated in the upregulationof IL-8 gene expression and also induces IL-8 release from theepithelial cells of the lung. In animal models of Chronic ObstructivePulmonary Disease induced by tobacco smoke exposure, both small moleculeinhibitors and protein inhibitors of HNE inhibit the inflammatoryresponse and the development of emphysema (see Wright, J. L. et al. Am.J. Respir. Crit. Care Med. 2002, 166, 954-960; and Churg, A. et al. Am.J. Respir. Crit. Care Med. 2003, 168, 199-207, which are incorporatedherein by reference in their entireties). Thus, HNE may play a role bothin matrix destruction and in amplifying inflammatory responses inchronic respiratory diseases where neutrophil influx is a characteristicfeature. Indeed, HNE is believed to play a role in several pulmonarydiseases, including chronic obstructive pulmonary disease (COPD), cysticfibrosis (CF), acute respiratory distress syndrome (ARDS), pulmonaryemphysema, pneumonia, and lung fibrosis. It is also implicated inseveral cardiovascular diseases in which tissue remodeling is involved,for example, in heart failure and the generation of ischaemic tissueinjury following acute myocardial infarction.

COPD is an umbrella term encompassing three different pathologicalconditions, all of which contribute to limitation of airflow: chronicbronchitis, emphysema, and small-airway disease. Generally all threewill exist to varying extents in patients presenting with COPD, and allthree may be due to neutrophil-mediated inflammation, as supported bythe increased number of neutrophils observed in bronchoalveolar leakage(BAL) fluids of COPD patients (see Thompson, A. B.; Daughton, D.; et al.Am. Rev. Respir. Dis. 1989, 140, 1527-1537, which is incorporated hereinby reference in its entirety). The major pathogenic determinant in COPDhas long been considered to be the protease-anti-protease balance (alsoknown as the “elastase:anti-elastase hypothesis”), in which an imbalanceof HNE and endogenous antiproteases such as α1-antitrypsin (α₁-AT),secretory leukocyte protease inhibitor (SLPI) and pre-elafin leads tothe various inflammatory disorders of COPD. Individuals that have agenetic deficiency of the protease inhibitor α1-antitrypsin developemphysema that increases in severity over time (see Laurrell, C. B.;Erikkson, S Scand. J. Clin. Invest. 1963 15, 132-140, which isincorporated herein by reference in its entirety). An excess of HNE istherefore destructive, leading to the breakdown of pulmonary morphologywith loss of elasticity and destruction of alveolar attachments ofairways in the lung (emphysema) whilst simultaneously increasingmicrovascular permeability and mucus hypersecretion (chronicbronchitis).

Several human neutrophil inhibitors have been disclosed so far in theart. In particular, International Patent Application Nos. WO 2011/110858and WO 2011/110859, which are incorporated herein by reference in theirentireties, describe some pyrimidine derivatives having human neutrophilelastase inhibitory properties and their use in therapy.

Although several HNE inhibitors have been disclosed so far as abovereported, there is still a need for further HNE inhibitors.Particularly, there is still a need for further HNE inhibitors endowedwith a high potency for HNE enzyme inhibition. Particularly advantageouswould also be the identification of further HNE inhibitors endowed witha high potency for HNE enzyme inhibition and which would show anappropriate developability profile as an inhalation treatment. Thepresent invention addresses the above mentioned needs by providing thecompounds of the invention.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompounds, which have human neutrophil elastase inhibitory properties,and salts of such a compound.

It is another object of the present invention to provide novelpharmaceutical compositions which contain such a compound or saltthereof.

It is another object of the present invention to provided novelcombinations of such a compound or salt thereof with another activeagent.

It is another object of the present invention to provide novel methodsof treating certain diseases and conditions by administering aneffective amount of such a compound or salt thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

wherein:

A is CH or N;

R₁ is selected from the group consisting of:

-   -   hydrogen;    -   (C₁-C₆)alkyl;    -   NR₇R₈(C₁-C₆)alkyl; (C₁-C₄)alkenyl;    -   phenyl(C₁-C₆)alkyl wherein such phenyl ring is optionally        substituted by NR₁₅R₁₆(C₁-C₆)alkyl or by        N⁺R₁₅R₁₆R₁₇(C₁-C₆)alkyl;    -   a group —CH₂(CH₂)_(n)OH;    -   a group —(CH₂)_(n)CONR₅R₆;    -   a group —(CH₂)_(n)SO₂NR₅R₆;    -   a group —CH₂—(CH₂)_(n)NR₅SO₂R₆;    -   a group —(CH₂)_(t)—(C₆H₄)—SO₂(C₁-C₄)alkyl;    -   a group —(CH₂)_(r)SO₂(C₁-C₄)alkyl wherein such (C₁-C₄)alkyl is        optionally substituted by a group —NR₁₅R₁₆ or —N⁺R₁₅R₁₆R₁₇;    -   a group —SO₂-phenyl wherein such phenyl ring is optionally        substituted by NR₇R₈(C₁-C₆)alkyl; and    -   a group —(CH₂)_(n)—W wherein W is a 5 or 6-membered heteroaryl        ring which is optionally substituted by a group        —SO₂(C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   t is zero, 1, 2 or 3;    -   r is zero, 1, 2, 3 or 4;    -   R₅ is selected in the group consisting of: hydrogen,        (C₁-C₆)alkyl,    -   NR₁₆R₁₅(C₁-C₆)alkyl and N⁺R₁₇R₁₅R₁₆(C₁-C₆)alkyl;    -   R₆ is hydrogen or (C₁-C₆)alkyl;    -   R₇ is selected in the group consisting of: hydrogen,        (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, —SO₂(C₁-C₄)alkyl, and        NR₁₆R₁₅(C₁-C₆)alkyl;    -   R₈ is hydrogen or (C₁-C₆)alkyl;    -   alternatively, R₇ and R₈, together with the nitrogen atom to        which they are attached, form a (C₅-C₇)heterocycloalkyl ring        system which is optionally substituted by one or more groups        (C₁-C₆) alkyl and oxo;    -   R₁₆ is hydrogen or (C₁-C₆)alkyl;    -   R₁₅ is hydrogen or (C₁-C₆)alkyl;    -   R₁₇ is hydrogen or (C₁-C₆)alkyl;        R₂ is hydrogen or —SO₂R₄, wherein R₄ is selected from:        optionally substituted (C₁-C₆)alkyl, hydroxyl(C₁-C₆)alkyl,        amino, mono- or di(C₁-C₄)alkylamino wherein (C₁-C₄)alkyl may be        optionally substituted, optionally substituted        (C₃-C₆)-cycloalkyl, halogen and optionally substituted phenyl;    -   R₁₄ is a group cyano or a group —C(O)—XR₃;    -   X is a divalent group selected from: —O—, —(CH₂)— and —NH—;    -   R₃ is a group selected in the list consisting of:        -   hydrogen;        -   (C₁-C₆)alkyl;        -   a group of formula [Alk¹]-Z,        -   wherein Alk¹ represents a (C₁-C₄)alkylene radical, and        -   Z is:        -   (i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen,            optionally substituted (C₁-C₆)alkyl or an optionally            substituted (C₃-C₆)cycloalkyl group; or, taken together with            the nitrogen to which they are attached, form an optionally            substituted monocyclic (C₅-C₇)heterocyclic ring which may            contain a further heteroatom selected from N, O and S;        -   or        -   (ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each            independently optionally substituted (C₁-C₆)alkyl or            optionally substituted (C₃-C₆)cycloalkyl group; or any two            of R₁₁, R₁₂ and R₁₃ taken together with the nitrogen to            which they are attached form an optionally substituted            monocyclic (C₅-C₇)heterocyclic ring which may contain a            further heteroatom selected from N, O and S and the other of            R₁₁, R₁₂ and R₁₃ is an optionally substituted (C₁-C₆)alkyl            or an optionally substituted (C₃-C₆)cycloalkyl group; and        -   a radical of formula —(CH₂)_(q)-[Q]-(CH₂)_(p) Z wherein Z is            as above defined, q is an integer ranging from zero to 3, p            is an integer ranging from zero to 3 and Q represents a            divalent group selected from: —O—, optionally substituted            phenylene, optionally substituted            (C₅-C₇)heterocycloalkylene, optionally substituted            (C₃-C₆)cycloalkyl and optionally substituted pyridinylene;

wherein if one or more groups N⁺R₁₁R₁₂R₁₃ (C₁-C₆)alkyl- or N⁺R₁₅R₁₆R₁₇(C₁-C₆)alkyl- are present, they form quaternary salts with apharmaceutically acceptable counter ion;

and wherein groups R₅, R₆, R₇, R₈, R₁₅, R₁₆, R₁₇, and n may assume thesame or different meanings at each occurrence, if present in more thanone group;

with the proviso that the compound of formula (I) is not:

-   5-(4-Cyanophenyl)-2-(2-dimethylaminoethyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid 2-dimethylaminoethyl ester;-   {2-[5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyloxy]ethyl}-trimethylammonium;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid;    and pharmaceutically acceptable salts thereof and N-oxides thereof    are inhibitors of HNE, and are useful in the treatment of diseases    or conditions in which HNE activity plays a part.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Thus, in one aspect, the present invention provides compounds of formula(I), and pharmaceutically acceptable salts thereof:

wherein:

A is CH or N;

R₁ is selected from the group consisting of:

-   -   hydrogen;    -   (C₁-C₆)alkyl;    -   NR₇R₈(C₁-C₆)alkyl;    -   (C₁-C₄)alkenyl;    -   phenyl(C₁-C₆)alkyl wherein such phenyl ring is optionally        substituted by NR₁₅R₁₆(C₁-C₆)alkyl or by        N⁺R₁₅R₁₆R₁₇(C₁-C₆)alkyl;    -   a group —CH₂(CH₂)_(n)OH;    -   a group —(CH₂)_(n)CONR₅R₆;    -   a group —(CH₂)_(n)SO₂NR₅R₆;    -   a group —CH₂—(CH₂)_(n)NR₅SO₂R₆;    -   a group —(CH₂)_(t)(C₆H₄)—SO₂(C₁-C₄)alkyl;    -   a group —(CH₂)_(t)SO₂(C₁-C₄)alkyl wherein such (C₁-C₄)alkyl is        optionally substituted by a group —NR₁₅R₁₆ or —N⁺R₁₅R₁₆R₁₇;    -   a group —SO₂-phenyl wherein such phenyl ring is optionally        substituted by NR₇R₈(C₁-C₆)alkyl; and    -   a group —(CH₂)n-W wherein W is a 5-6-membered heteroaryl ring        which is optionally substituted by a group —SO₂(C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   t is zero, 1, 2 or 3;    -   r is zero, 1, 2, 3 or 4;    -   R₅ is selected in the group consisting of: hydrogen,        (C₁-C₆)alkyl, NR₁₆R₁₅(C₁-C₆)alkyl and N⁺R₁₇R₁₅R₁₆(C₁-C₆)alkyl;    -   R₆ is hydrogen or (C₁-C₆)alkyl;    -   R₇ is selected in the group consisting of: hydrogen,        (C₁-C₆)alkyl,    -   (C₁-C₆)alkylcarbonyl, —SO₂(C₁-C₄)alkyl, and NR₁₆R₁₅(C₁-C₆)alkyl;    -   R₈ is hydrogen or (C₁-C₆)alkyl;    -   alternatively, R₇ and R₈, together with the nitrogen atom to        which they are attached, form a (C₅-C₇)heterocycloalkyl ring        system which is optionally substituted by one or more groups        (C₁-C₆)alkyl and oxo;    -   R₁₆ is hydrogen or (C₁-C₆)alkyl;    -   R₁₅ is hydrogen or (C₁-C₆)alkyl;    -   R₁₇ is hydrogen or (C₁-C₆)alkyl;        R₂ is hydrogen or —SO₂R₄, wherein R₄ is selected from:        optionally substituted (C₁-C₆)alkyl, hydroxyl(C₁-C₆)alkyl,        amino, mono- or di(C₁-C₄)alkylamino wherein (C₁-C₄)alkyl may be        optionally substituted, optionally substituted        (C₃-C₆)-cycloalkyl, halogen and optionally substituted phenyl;    -   R₁₄ is a group cyano or a group —C(O)—XR₃;    -   X is a divalent group selected from: —O—, —(CH₂)— and —NH—;    -   R₃ is a group selected in the list consisting of:        -   hydrogen;        -   (C₁-C₆)alkyl;        -   a group of formula [Alk¹]-Z,        -   wherein Alk¹ represents a (C₁-C₄)alkylene radical, and        -   Z is:        -   (i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen,            optionally substituted (C₁-C₆)alkyl or an optionally            substituted (C₃-C₆)cycloalkyl group; or, taken together with            the nitrogen to which they are attached, form an optionally            substituted monocyclic (C₅-C₇)heterocyclic ring which may            contain a further heteroatom selected from N, O and S;        -   or        -   (ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each            independently optionally substituted (C₁-C₆)alkyl or            optionally substituted (C₃-C₆)cycloalkyl group; or any two            of R₁₁, R₁₂ and R₁₃ taken together with the nitrogen to            which they are attached form an optionally substituted            monocyclic (C₅-C₇)heterocyclic ring which may contain a            further heteroatom selected from N, O and S and the other of            R₁₁, R₁₂ and R₁₃ is an optionally substituted (C₁-C₆)alkyl            or an optionally substituted (C₃-C₆)cycloalkyl group; and        -   a radical of formula —(CH₂)_(q)-[Q]-(CH₂)_(p) Z wherein Z is            as above defined, q is an integer ranging from zero to 3, p            is an integer ranging from zero to 3 and Q represents a            divalent group selected from: —O—, optionally substituted            phenylene, optionally substituted            (C₅-C₇)heterocycloalkylene, optionally substituted            (C₃-C₆)cycloalkyl and optionally substituted pyridinylene;

wherein if one or more groups N⁺R₁₁R₁₂R₁₃(C₁-C₆)alkyl- orN⁺R₁₅R₁₆R₁₇(C₁-C₆)alkyl- are present, they form quaternary salts with apharmaceutically acceptable counter ion;

and wherein groups R₅, R₆, R₇, R₈, R₁₅, R₁₆, R₁₇, and n may assume thesame or different meanings at each occurrence, if present in more thanone group;

with the proviso that the compound of formula (I) is not:

-   5-(4-Cyanophenyl)-2-(2-dimethylaminoethyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid 2-dimethylaminoethyl ester;-   {2-[5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyloxy]ethyl}-trimethylammonium;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid;

and pharmaceutically acceptable salts thereof and N-oxides thereof.

In one embodiment, the present invention provides a compound of formula(ID):

wherein

A is CH or N;

R₁ is selected from the group consisting of:hydrogen;

(C₁-C₆)alkyl;

NR₇R₈(C₁-C₆)alkyl;

-   -   (C₁-C₄)alkenyl;

phenyl(C₁-C₆)alkyl;

a group —CH₂(CH₂)_(n)OH;

a group —(CH₂)_(n)CONR₅R₆;

a group —(CH₂)_(n)SO₂NR₅R₆; and

a group —CH₂—(CH₂)_(n)NR₅SO₂R₆;

n is 1, 2 or 3;

R₅ is hydrogen or (C₁-C₆)alkyl;

R₆ is hydrogen or (C₁-C₆)alkyl;

R₇ is hydrogen or (C₁-C₆)alkyl;

R₈ is hydrogen or (C₁-C₆)alkyl;

R₂ is hydrogen or —SO₂R₄, wherein R₄ is selected from: optionallysubstituted (C₁-C₆)alkyl, hydroxyl(C₁-C₆)alkyl, amino, mono- ordi(C₁-C₄)alkylamino wherein (C₁-C₄)alkyl may be optionally substituted,optionally substituted C₃-C₆-cycloalkyl, halogen and optionallysubstituted phenyl;

R₁₄ is a group a group —C(O)—XR₃;

X is a divalent group selected from: —O—, —(CH₂)— and —NH—;

R₃ is a group selected from:

-   -   (C₁-C₆)alkyl;    -   a group of formula -[Alk¹]-Z,    -   wherein Alk¹ represents a (C₁-C₄)alkylene radical, and    -   Z is:    -   (i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen,        optionally substituted (C₁-C₆)alkyl or an optionally substituted        (C₃-C₆)cycloalkyl group; or, taken together with the nitrogen to        which they are attached, form an optionally substituted        monocyclic (C₅-C₇)heterocyclic ring which may contain a further        heteroatom selected from N, O and S;    -   or    -   (ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each        independently optionally substituted (C₁-C₆)alkyl or optionally        substituted (C₃-C₆)cycloalkyl group; or any two of R₁₁, R₁₂ and        R₁₃ taken together with the nitrogen to which they are attached        form an optionally substituted monocyclic (C₅-C₇)heterocyclic        ring which may contain a further heteroatom selected from N, O        and S and the other of R₁₁, R₁₂ and R₁₃ is an optionally        substituted (C₁-C₆)alkyl or an optionally substituted        (C₃-C₆)cycloalkyl group; and    -   a radical of formula —(CH₂)_(q)-[Q]-(CH₂)_(p) Z wherein Z is as        above defined, q is an integer ranging from zero to 3, p is an        integer ranging from zero to 3 and Q represents a divalent group        selected from: —O—, optionally substituted phenylene, optionally        substituted (C₅-C₇)heterocycloalkylene, optionally substituted        (C₃-C₆)cycloalkyl and optionally substituted pyridinylene;

or a pharmaceutically acceptable salt thereof;

with the proviso that the compound of formula (I) is not:

-   5-(4-Cyanophenyl)-2-(2-dimethylaminoethyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid 2-dimethylaminoethyl ester; or-   {2-[5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyloxy]ethyl}-trimethylammonium.

Compounds of formula (I) may be prepared in the form of salts,particularly pharmaceutically acceptable salts, N-oxides, hydrates,solvates and polymorphs thereof. Any reference to a compound herein, orreference to “compounds of the invention”, “compounds of formula (I)”,and the like includes such compounds whether or not in salt, N-oxide,hydrate, solvate or polymorphic form.

It will be appreciated by a person skilled in the art that certaingroups included in compounds of formula (I) may exist in one or moretautomeric forms. The present invention includes within its scope allsuch tautomeric forms, including mixtures. In particular, it will beappreciated by a person skilled in the art that compounds of formula(I), when R₁ is hydrogen, may exist in two tautomeric forms as belowreported:

Both tautomeric forms are intended to be included within the scope ofcompounds of the present invention.

Compounds of the present invention may be used in the treatment orprevention of diseases in which HNE is implicated, for example chronicobstructive pulmonary disease (COPD), bronchiectasis, chronicbronchitis, lung fibrosis, pneumonia, acute respiratory distresssyndrome (ARDS), pulmonary emphysema, smoking-induced emphysema, andcystic fibrosis.

Hence other aspects of the invention include (i) pharmaceuticalcompositions comprising a compound of the present invention and apharmaceutically acceptable carrier or excipient; and (ii) the use of acompound of the present invention for the manufacture of a medicamentfor the treatment or prevention of a disease or condition in which HNEis implicated.

The term “(C_(a)-C_(b))alkyl” wherein a and b are integers refers to astraight or branched chain alkyl radical having from a to b carbonatoms. Thus when a is 1 and b is 6, for example, the term includesmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, n-pentyl and n-hexyl.

The term “(C_(a)-C_(b))alkenyl” wherein a and b are integers refers to astraight or branched chain alkenyl moiety having from a to b carbonatoms having at least one double bond of either E or Z stereochemistrywhere applicable. Thus when a is 2 and b is 6, for example, the termincludes, for example, vinyl, allyl, 1- and 2-butenyl and2-methyl-2-propenyl.

The expressions “NR₁₅R₁₆(C_(a)-C_(b))alkyl” or“NR₇R₈(C_(a)-C_(b))alkyl”, wherein a and b are as above defined, referto the above defined “(C_(a)-C_(b))alkyl” groups wherein one hydrogenatom is replaced by a group —NR₁₅R₁₆ or —NR₇R₈ respectively.

The expression “N⁺R₁₅R₁₆R₁₇(C_(a)-C_(b))alkyl” wherein a and b are asabove defined, refer to the above defined “(C_(a)-C_(b))alkyl” groupswherein one hydrogen atom is replaced by a group —N⁺R₁₅R₁₆R₁₇.

The expressions “mono (C_(a)-C_(b))alkyl” or “di (C_(a)-C_(b))alkylamino”, wherein a and b are integers, refer to an amino group wherein,respectively, one or both hydrogen atoms are replaced by a group(C_(a)-C_(b))alkyl.

The expression “phenyl(C_(a)-C_(b))alkyl” refers to the above defined“(C_(a)-C_(b))alkyl” radicals wherein one hydrogen atom is replaced by aphenyl group.

The term “divalent (C_(a)-C_(b))alkylene radical” wherein a and b areintegers refers to a saturated hydrocarbon chain having from a to bcarbon atoms as above defined and two unsatisfied valences.

The term “(C_(a)-C_(b))cycloalkyl”, wherein a and b are integers, refersto saturated monocyclic hydrocarbon groups containing from a to b ringcarbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The expression “(C_(a)-C_(b))heterocycloalkyl” refers to monocyclic(C_(a)-C_(b))cycloalkyl groups, in which at least one ring carbon atomis replaced by a heteroatom (e.g. N, NH, S, or O). Examples of(C_(a)-C_(b))heterocycloalkyl are represented by: pyrrolidinyl,thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, andthiomorpholinyl.

By analogy, the expression “(C_(a)-C_(b))heterocycloalkylene” refers toa divalent (C_(a)-C_(b))heterocycloalkyl radical (such as for examplepyrrolidinene) wherein “(C_(a)-C_(b))heterocycloalkyl group is as abovedefined.

The expression “heteroaryl” refers to mono or bi-cyclic ring systemswith 5 to 11 ring atoms, in which at least one ring is aromatic and inwhich at least one ring atom is a heteroatom (e.g. N, NH, S, or O).

Examples of suitable 5 and 6-membered heteroaryl monocyclic systemsinclude, for instance thiophene (thiophenyl), benzene (phenyl), pyrrole(pyrrolyl), pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole(isoxazolyl), oxazole (oxazolyl), isothiazole (isothiazolyl), thiazole(thiazolyl), pyridine (pyridinyl), imidazolidine (imidazolidinyl), furan(furanyl) radicals, and the like.

The term “(C_(a)-C_(b)) alkoxyl” wherein a and b are integers, refers tostraight-chained and branched alkoxy groups wherein the number ofconstituent carbon atoms is in the range from a to b. Particular alkylgroups are methoxyl, ethoxyl, n-propoxyl, isopropoxyl and t-butoxyl.

The symbol “—C₆H₄—” indicates a divalent phenylene ring radical.

The expression “(C_(a)-C_(b))alkylcarbonyl” refers to—CO(C_(a)-C_(b))alkyl groups wherein the group “(C_(a)-C_(b))alkyl” hasthe meaning above defined.

The expressions “hydroxy(C_(a)-C_(b))alkyl” refer to the above defined“(C_(a)-C_(b))alkyl” radicals wherein one hydrogen atom is replaced by agroup —OH.

Unless otherwise specified, the term “substituted” as applied to anymoiety herein means substituted with up to four compatible substituents,each of which independently may be, for example, (C₁-C₆)alkyl,(C₁-C₆)alkoxyl, hydroxyl, hydroxyl-C₁-C₆-alkyl, halo (including fluoro,bromo, and chloro), trifluoromethyl, trifluoromethoxy. An “optionalsubstituent” may be one of the foregoing substituent groups.

The term “salt” includes base addition and acid addition salts.

The term “Pharmaceutically acceptable salts” refers to derivatives ofcompounds of formula (I) wherein the parent compound is suitablymodified by converting any of the free acid or basic group, if present,into the corresponding addition salt with any base or acidconventionally intended as being pharmaceutically acceptable.

Compounds of the present invention which are acidic can form salts,including pharmaceutically acceptable salts, with bases such as alkalimetal hydroxides, e.g. sodium and potassium hydroxides; alkaline earthmetal hydroxides, e.g., calcium, barium, and magnesium hydroxides; withorganic bases, e.g., N-methyl-D-glucamine, cholinetris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine, and the like. Those compounds which are basiccan form salts, including pharmaceutically acceptable salts withinorganic acids, e.g. with hydrohalic acids such as hydrochloric orhydrobromic acids, sulfuric acid, nitric acid or phosphoric acid and thelike, and with organic acids e.g. with acetic, tartaric, succinic,fumaric, maleic, malic, salicylic, citric, methanesulphonic,p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, andmandelic acids, and the like. Those compounds which have quaternarynitrogen can also form quaternary salts with a pharmaceuticallyacceptable counter-ion such as chloride, bromide, acetate, formate,p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bissulfonate, methanesulfonate, xinafoate, and the like.

Where the compounds of the invention have at least one stereogeniccenter, they may exist as enantiomers. When the compounds according tothe invention possess two or more stereogenic centers, they mayadditionally exist as diastereoisomers. It is to be understood that allsuch isomers and mixtures thereof in any proportion are encompassedwithin the scope of the present invention.

It will be apparent that compounds of general formula (I) contain atleast contain one stereogenic center, namely represented by the carbonatom (1) with an asterisk below, and therefore exist as opticalstereoisomers:

In one embodiment, the present invention is directed to compounds offormula (I)′, which are compounds of formula (I) as above defined wherethe absolute configuration of carbon (1) is that shown here below:

In another embodiment, the present invention is directed to compounds offormula (I)″, which are compounds of formula (I) as above defined wherethe absolute configuration of carbon (1) is that shown herebelow:

The absolute configuration for carbon (1) is assigned on the basis ofCahn-Ingold-Prelog nomenclature based on groups' priorities.

It is to be understood that all preferred groups or embodimentsdescribed here below for compounds of formula (I) may be combined amongeach other and apply as well to compounds of formula (I)′, (I)″, (IA),(IB), (IC), and (IE), mutatis mutandis.

In one embodiment, for compounds of formula (I) A is CH.

In one embodiment, R₂ is hydrogen or a group —SO₂R₄, wherein R₄ is(C₁-C₆)alkyl. In a preferred embodiment, R₂ is hydrogen.

In one embodiment, R₄ is optionally substituted (C₁-C₆)alkyl. In anotherembodiment, R₄ is (C₁-C₆)alkyl.

In one embodiment, R₁₄ is a group cyano or a group —C(O)—XR₃. In apreferred embodiment, R₁₄ is a group —C(O)—XR₃.

In one embodiment, X is a divalent group —O— or —NH—. In anotherembodiment, X is a divalent —O—.

In one embodiment, R₃ is a group selected from the group consisting of:

hydrogen;

(C₁-C₆)alkyl; and

a radical of formula -[Alk¹]-Z wherein Alk¹ represents a (C₁-C₄)alkyleneradical and Z is:

(i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen, optionallysubstituted (C₁-C₆)alkyl or an optionally substituted (C₃-C₆)cycloalkylgroup; or, taken together with the nitrogen to which they are attachedform an optionally substituted monocyclic (C₅-C₇)heterocyclic ring whichmay contain a further heteroatom selected from N, O and S; or

(ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each independentlyoptionally substituted (C₁-C₆)alkyl or optionally substituted(C₃-C₆)cycloalkyl group; or any two of R₁₁, R₁₂ and R₁₃ taken togetherwith the nitrogen to which they are attached form an optionallysubstituted monocyclic (C₅-C₇)heterocyclic ring which may contain afurther heteroatom selected from N, O and S and the other of R₁₁, R₁₂and R₁₃ is an optionally substituted (C₁-C₆)alkyl or an optionallysubstituted (C₃-C₆)cycloalkyl group.

In a preferred embodiment, R₃ is a group selected in the list consistingof:

-   -   hydrogen;    -   (C₁-C₆)alkyl; and    -   a radical of formula -[Alk¹]-Z wherein Alk¹ represents a        (C₁-C₄)alkylene radical and Z is:

(i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen, (C₁-C₆)alkylor (C₃-C₆)cycloalkyl group; or, taken together with the nitrogen towhich they are attached form a monocyclic (C₅-C₇)heterocyclic ring whichmay contain a further heteroatom selected from N, O and S;

or

(ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each independently(C₁-C₆)alkyl or (C₃-C₆)cycloalkyl group; or any two of R₁₁, R₁₂ and R₁₃taken together with the nitrogen to which they are attached form amonocyclic (C₅-C₇)heterocyclic ring which may contain a furtherheteroatom selected from N, O and S and the other of R₁₁, R₁₂ and R₁₃ is(C₁-C₆)alkyl or a (C₃-C₆)cycloalkyl group.

In another preferred embodiment, R₃ is a group selected in the listconsisting of:

hydrogen;

(C₁-C₆)alkyl; and

a radical of formula -[Alk¹]-Z wherein Alk¹ represents a (C₁-C₄)alkyleneradical and Z is:

(i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl;

or

(ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each independentlyoptionally substituted (C₁-C₆)alkyl.

In a further preferred embodiment, R₃ is (C₁-C₆)alkyl.

In a still preferred embodiment, embodiment, R₃ is a group selected inthe list consisting of:

hydrogen;

(C₁-C₆)alkyl; and

a radical of formula -[Alk¹]-Z wherein Alk¹ represents a (C₁-C₄)alkyleneradical and Z is:

(i) —NR₉R₁₀ wherein R₉ and R₁₀ are independently hydrogen or optionallysubstituted (C₁-C₆)alkyl;

or

(ii) —N⁺R₁₁R₁₂R₁₃ wherein R₁₁, R₁₂ and R₁₃ are each independentlyoptionally substituted (C₁-C₆)alkyl;

and X is a divalent —O—.

In one embodiment, for compounds of formula (I), R₁ is hydrogen or is agroup selected from: (C₁-C₆)alkyl, NR₇R₈(C₁-C₆)alkyl, (C₁-C₄)alkenyl,phenyl(C₁-C₆)alkyl, and a group —(CH₂)_(n)CONR₅R₅R₆.

In a preferred embodiment, for compounds of formula (I), R₁ is hydrogenor is a group selected from: —CH₂(CH₂)_(n)OH, —(CH₂)_(n)CONR₅R₆,—(CH₂)_(n)SO₂NR₅R₆, and —CH₂—(CH₂)_(n)NR₅SO₂R₆.

In another preferred embodiment, R₁ is hydrogen or is a group—(CH₂)_(n)CONR₅R₆. In a still further embodiment, R₁ is hydrogen.

In a preferred embodiment, R₁ selected from the group consisting of:hydrogen, (C₁-C₆)alkyl, NR₇R₈(C₁-C₆)alkyl, (C₁-C₄)alkenyl,phenyl(C₁-C₆)alkyl wherein such phenyl ring is optionally substituted bya group NR₁₅R₁₆(C₁-C₆)alkyl- or by a group —(C₁-C₆)alkylN⁺R₁₅R₁₆R₁₇,—(CH₂)_(n)CONR₅R₆, —CH₂—(CH₂)_(n)NR₅SO₂R₆,—(CH₂)_(t)—(C₆H₄)—SO₂(C₁-C₄)alkyl, —(CH₂)_(r)SO₂(C₁-C₄)alkyl whereinsuch (C₁-C₄)alkyl is optionally substituted by a group —NR₁₅R₁₆ or—N⁺R₁₅R₁₆R₁₇, —SO₂-phenyl wherein such phenyl ring is optionallysubstituted by a group —(C₁-C₆)alkyl NR₇R₈, and —(CH₂)_(n)W wherein W isa 5-6-membered heteroaryl ring which is optionally substituted by agroup —SO₂(C₁-C₄)alkyl.

In a preferred embodiment, R₁ selected from the group consisting of:hydrogen, (C₁-C₆)alkyl, NR₇R₈(C₁-C₆)alkyl, phenyl(C₁-C₆)alkyl whereinsuch phenyl ring is optionally substituted by a groupNR₁₅R₁₆(C₁-C₆)alkyl- or by a group —(C₁-C₆)alkylN⁺R₁₅R₁₆R₁₇,—(CH₂)_(n)CONR₅R₆, —CH₂—(CH₂)_(n)NR₅SO₂R₆,—(CH₂)_(t)—(C₆H₄)—SO₂(C₁-C₄)alkyl, and —(CH₂)_(r)SO₂(C₁-C₄)alkyl whereinsuch (C₁-C₄)alkyl is optionally substituted by a group —NR₁₅R₁₆ or—N⁺R₁₅R₁₆R₁₇.

In another preferred embodiment, R₁ selected from the group consistingof: hydrogen, —(CH₂)_(n)CONR₅R₆, —CH₂—(CH₂)_(n)NR₅SO₂R₆, and—(CH₂)_(r)SO₂(C₁-C₄)alkyl wherein such (C₁-C₄)alkyl is optionallysubstituted by a group —NR₁₅R₁₆ or —N⁺R₁₅R₁₆R₁₇.

In one embodiment, a compound of formula (IA) is provided

wherein R₁₄ is —COXR₃, X is oxygen, R₂ is hydrogen, A is CH, and theother groups are as above defined.

In another embodiment, a compound of formula (IB) is provided

wherein R₁₄ is —COXR₃, X is NH, R₂ is hydrogen, A is CH, and the othergroups are as above defined.

In a further embodiment, a compound of formula (IC) is provided

wherein R₁₄ is —COXR₃, R₁ is hydrogen, R₂ is hydrogen, A is CH, and theother groups are as above defined.

In a further embodiment, a compound of formula (IE) is provided which isa compound of formula (I), wherein R₁₄ is a group —CN, R₂ is hydrogen, Ais CH, and the other groups are as above defined.

In another embodiment, a compound of the present invention is selectedin the group consisting of:

-   5-(4-Cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   2-Carbamoylmethyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2-(2-dimethylamino-propyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   2-Benzyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   2-Allyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;    and pharmaceutically acceptable salts thereof.

In still another embodiment, a compound of the present invention isselected in the group consisting of:

-   5-(4-Cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   2-Carbamoylmethyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2-(2-dimethylamino-propyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   2-Benzyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   2-Allyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   (R)-5-(4-Cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid 2-dimethylamino-ethyl ester;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid 3-dimethylamino-propyl ester;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid ethylamide;-   5-(4-Cyano-2-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-2-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile;-   5-(4-Cyano-phenyl)-2-(4-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   (R)-5-(4-Cyano-phenyl)-2-(4-methanesulfonyl-benzyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   (R)-5-(4-Cyano-phenyl)-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-benzenesulfonyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   (R)-5-(4-Cyano-phenyl)-2-[2-(4-methanesulfonyl-phenyl)-ethyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-(4-dimethylaminomethyl-benzyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   {4-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-ylmethyl]-benzyl}-trimethyl-ammonium    bromide;-   5-(4-Cyano-phenyl)-2-(5-methanesulfonyl-pyridin-2-ylmethyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-{[(3-dimethylamino-propyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   [2-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)-ethyl]-trimethyl-ammonium    bromide;-   [3-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)propyl]-trimethyl-ammonium    bromide;-   5-(4-Cyano-phenyl)-2-{[(4-dimethylamino-butyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-{[(5-dimethylamino-pentyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   [4-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)-butyl]-trimethylammonium    bromide;-   [5-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)pentyl]-trimethyl-ammonium    bromide;-   (R)-[5-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)pentyl]-trimethyl-ammonium    chloride;-   2-[3-(Acetyl-methyl-amino)-propyl]-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;-   5-(4-Cyano-phenyl)-2-[3-(methanesulfonyl-methyl-amino)-propyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;

(3-{3-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumtoluene-4-sulfonate;

-   (R)-(3-{3-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammonium    chloride;-   5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile;

(3-{3-[6-Cyano-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumtoluene-4-sulfonate;

-   (R)-5-(4-Cyano-phenyl)-2-{[(5-dimethylamino-pentyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic    acid methyl ester;    and pharmaceutically acceptable salts thereof.

The therapeutic utility of the present compounds is pertinent to anydisease that is known to be at least partially mediated by the action ofhuman neutrophil elastase. For example, the present compounds may bebeneficial in the treatment of chronic obstructive pulmonary disease(COPD), cystic fibrosis (CF), bronchiectasis, acute respiratory distresssyndrome (ARDS), pulmonary emphysema, pneumonia. and lung fibrosis.

Compounds of the present invention are useful for treatment ofinflammatory respiratory disorders, for example asthma (mild, moderateor severe), steroid resistant asthma, bronchitis, chronic obstructivepulmonary disease (COPD), cystic fibrosis (CF), pulmonary edema,pulmonary embolism, pneumonia, pulmonary sarcoidosis, pulmonaryemphysema, silicosis, pulmonary fibrosis, pulmonary hypertension,respiratory failure, acute respiratory distress syndrome (ARDS),emphysema, chronic bronchitis, tuberculosis, aspergillosis and otherfungal infections, hypersensitivity pneumonitis, vasculitic andthrombotic disorders of the lung vasculature, antitussive activityincluding treatment of chronic cough associated with inflammatory andsecretory conditions of the airways, infection due to respiratorysyncytial virus, influenza, coronavirus (including severe acuterespiratory syndrome, SARS) and adenovirus, bronchiectasis and lungcancer.

The present invention is also concerned with pharmaceutical formulationscomprising, as an active ingredient, a compound of the invention. Othercompounds may be combined with compounds of this invention for theprevention and treatment of inflammatory diseases of the lung. Thus, thepresent invention is also concerned with pharmaceutical compositions forpreventing and treating inflammatory diseases of the lung comprising atherapeutically effective amount of a compound of the invention and oneor more other therapeutic agents.

Suitable therapeutic agents for a combination therapy with compounds ofthe invention include: (1) a corticosteroid, for example budesonide,beclomethasone, beclomethasone (e.g., as the mono or the dipropionateester), flunisolide, fluticasone (e.g. as the propionate or furoateester), Ciclesonide, mometasone (e.g. as the furoate ester), mometasonedesonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinoloneacetonide, fluocinonide, clocortolone, tipredane, prednicarbate,alclometasone dipropionate, halometasone, rimexolone, deprodonepropionate, triamcinolone, betamethasone, fludrocoritisone,desoxycorticosterone, rofleponide, etiprednol dicloacetate and the like.Steroid drugs can additionally include steroids in clinical orpre-clinical development for respiratory diseases such as GW-685698,GW-799943, GSK 870086, QAE397, NCX-1010, NCX-1020, NO-dexamethasone,PL-2146, NS-126 (formerly ST-126). Steroid drugs can also additionallyinclude next generation molecules in development with reduced sideeffect profiles such as selective glucocorticoid receptor agonists(SEGRAs), including ZK-216348 and AZD5423; (2) a β2-adrenoreceptoragonist, such as albuterol, bambuterol, terbutaline, fenoterol,formoterol, formoterol fumarate, salmeterol, salmeterol xinafoate,arformoterol, arfomoterol tartrate, indacaterol (QAB-149), carmoterol,BI 1744 CL, GSK159797 (milveterol), GSK59790, GSK159802, GSK642444(vilanterol), GSK678007, GSK96108, clenbuterol, procaterol, bitolterol,LAS100977 (abediterol), BI1744CL (olodaterol) and brodxaterol; (3) aleukotriene modulator, for example montelukast, zafirlukast orpranlukast; (4) anticholinergic agents, for example selectivemuscarinic-3 (M3) receptor antagonists such as ipratropium bromide,tiotropium, tiotropium bromide (Spiriva®), glycopyrronium bromide,aclidinium bromide, LAS34273, GSK656398, GSK233705, GSK 573719(umeclidinium), LAS35201, QAT370 and oxytropium bromide; (5)phosphodiesterase-IV (PDE-IV) inhibitors, for example roflumilast,cilomilast or theophylline; (6) an antitussive agent, such as codeine ordextramorphan; and (7) a non-steroidal anti-inflammatory agent (NSAID),for example ibuprofen or ketoprofen; (8) a mucolytic, for example Nacetyl cysteine or fudostein; (9) a expectorant/mucokinetic modulator,for example ambroxol, hypertonic solutions (e.g. saline or mannitol) orsurfactant; (10) a peptide mucolytic, for example recombinant humandeoxyribonoclease I (dornase-alfa and rhDNase) or helicidin; (11)antibiotics, for example azithromycin, tobramycin and aztreonam; (12)p38 Mitogen Activated Protein (MAP) kinase inhibitors, such as GSK856553 and GSK 681323; (13) inhibitors of Janus Kinases (JAK) such asCP-690550 or GLPG0634; (14) Spleen Tyrosine Kinase (SYK) inhibitors suchas R406, R343 or PRT062607; (15) inhibitors of delta and/or gammaisoforms of Phosphatidylinositol 3-kinase (PI3K); and (16)anti-retroviral agents such as ribavirin, zanamivir or laninamivir.

In one aspect, the present invention provides for the use of inhaledadministration of compounds of the invention in combination with otheranti-inflammatory drugs and bronchodilator drug combinations (i.e.triple combination product), including but not limited to salmeterolxinafoate/fluticasone propionate (Advair/Seretide®), formoterolfumarate/budesonide (Symbicort®), formoterol fumarate/mometasonefuroate, formoterol fumarate/beclometasone dipropionate (Foster®),formoterol fumarate/fluticasone propionate (FlutiForm®),Indacaterol/mometasone furoate, Indacaterol/QAE-397, GSK159797/GSK685698, GSK159802/GSK 685698, GSK642444/GSK 685698, formoterolfumarate/ciclesonide, and arformoterol tartrate/ciclesonide.

In another aspect, the present invention provides for the use of inhaledadministration of compounds of the invention in combination with otherbronchodilator drug combinations, particularly B2 agonist/M3 antagonistcombinations (i.e. triple combination product), including but notlimited to salmeterol xinafoate/tiotropium bromide, formoterolfumarate/tiotropium bromide, BI 1744 CL/tiotropium bromide,indacaterol/NVA237, indacterol/QAT-370, formoterol/LAS34273,GSK159797/GSK 573719, GSK159802/GSK 573719, GSK642444/GSK 573719,GSK159797/GSK 233705, GSK159802/GSK 233705, and GSK642444/GSK 233705.

The weight ratio of the first and second active ingredients may bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used.

The magnitude of a prophylactic or therapeutic dose of a compound of thepresent invention will, of course, vary with the nature of the severityof the condition to be treated and with the particular compound and itsroute of administration, and will generally be determined by clinicaltrial as required in the pharmaceutical art. It will also vary accordingto the age, weight and response of the individual patient. In general,the daily dose range will lie within the range of from about 0.001 mg toabout 100 mg per kg body weight of a mammal, preferably 0.01 mg to about50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single ordivided doses. On the other hand, it may be necessary to use dosagesoutside these limits in some cases.

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of the invention and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of theinvention encompass any composition made by admixing a compound of theinvention, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

The pharmaceutical compositions of the present invention comprise acompound of the invention as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dosage of a compound ofthe present invention. In therapeutic use, the active compound may beadministered by any convenient, suitable or effective route. Suitableroutes of administration are known, and include oral, intravenous,rectal, parenteral, topical, ocular, nasal, buccal and pulmonary (byinhalation).

Compositions suitable for administration by inhalation are known, andmay include carriers and/or diluents that are known for use in suchcompositions. The composition may contain 0.01-99% by weight of activecompound. Preferably, a unit dose comprises the active compound in anamount of 1 μg to 10 mg.

The most suitable dosage level may be determined by any known suitablemethod. It will be understood, however, that the specific amount for anyparticular patient will depend upon a variety of factors, including theactivity of the specific compound that is used, the age, body weight,diet, general health and sex of the patient, time of administration, theroute of administration, the rate of excretion, the use of any otherdrugs, and the severity of the disease to be treated.

For delivery by inhalation, the active compound is preferably in theform of microparticles. They may be prepared by a variety of techniques,including spray-drying, freeze-drying and micronization.

By way of example, a composition of the present invention may beprepared as a suspension for delivery from a nebulizer or as an aerosolin a liquid propellant, for example for use in a pressurized metereddose inhaler (PMDI). Propellants suitable for use in a PMDI are known tothe skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22(CCl2F2), and HFA-152 (CH4F2 and isobutane).

In a preferred embodiment of the present invention, a composition of theinvention is in dry powder form, for delivery using a dry powder inhaler(DPI). Many types of DPI are known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, a preferred composition is:

Compound of the invention 24 mg/canister   Lecithin, NF Liq. Conc. 1.2mg/canister   Trichlorofluoromethane, NF 4.025 g/canister  Dichlorodifluoromethane, NF 12.15 g/canister.  

Compounds of the present invention may be used in combination with otherdrugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which present compoundsare useful. Such other drugs may be administered, by a route and in anamount commonly used therefore, contemporaneously or sequentially with acompound of the invention. When a compound of the present invention isused contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe invention is preferred. Accordingly, the pharmaceutical compositionsof the invention include those that also contain one or more otheractive ingredients, in addition to a compound of the present invention.

The agents of the present invention may be administered in inhaled form.Aerosol generation can be carried out using, for example,pressure-driven jet atomizers or ultrasonic atomizers, preferably usingpropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from, for example, inhalation capsules orother “dry powder” delivery systems.

The active compounds may be dosed as described depending on the inhalersystem used. In addition to the active compounds, the administrationforms may additionally contain excipients, such as, for example,propellants (e.g. Frigen in the case of metered aerosols),surface-active substances, emulsifiers, stabilizers, preservatives,flavorings, fillers (e.g. lactose in the case of powder inhalers) or, ifappropriate, further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g. Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inparticular in the case of powder inhalers, a number of technicalsolutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or theinhalers for example as described EP-A-0505321, which is incorporatedherein by reference).

Methods of Synthesis.

In one aspect of the present invention, a process for the preparation ofcompounds of the invention (Ia), i.e. compounds of formula (I) whereinR1 is hydrogen and R14 is —COXR3, and of compounds of the invention offormula (Ib), i.e. compounds of formula (I) wherein R1 is not hydrogenand R14 is —COXR3, is provided, according to general synthetic routesreported in Scheme A here below.

Compounds of formula (IV) may be prepared from compounds of formula(III) by reaction with ethyl chloroformate in the presence of a basesuch as triethylamine in a solvent such as THF at a temperature of from0° C. to reflux. Compounds of formula (IV) may be transformed intocompounds of formula (Ia) by heating in an appropriate solvent. Suitableconditions include the use of a solvent such as IMS and heating usingmicrowave irradiation at a temperature of up to 150° C. Compounds offormula (Ia), which are compounds of formula (I) wherein R₁₄ is C(O)XR₃and R₁ is H, may be converted into compounds of formula (Ib), which arecompounds of formula (I) wherein R₁₄ is —C(O)XR₃, by reaction with analkyl halide (VI) of formula R₁—X′ such as an alkyl bromide in a solventsuch as DMF in the presence of a base such as cesium carbonate at atemperature of from room temperature to 100° C.

Compounds of formula (III) wherein R₃ is (C₁-C₆)alkyl, may be preparedaccording to Scheme B below:

Compounds formula (VIII) may be reacted with a benzaldehyde such as4-cyanobenzaldehyde and an acetoacetate such as ethyl acetoacetate inthe presence of an acid such as TMS-polyphosphate in a solvent such asTHF at a temperature of from room temperature to reflux to givecompounds of formula (VII), wherein R₃ is (C₁-C₆)alkyl and the othergroups are as define as for compounds of formula (I). Compounds offormula (III) may be prepared from compounds of formula (VII) byreaction with an oxidizing agent such as urea hydrogen peroxide followedby in-situ treatment with hydrazine hydrate in IMS.

The skilled person may introduce, where appropriate, suitable variationsto the conditions specifically described in the experimentaldescriptions in order to adapt the synthetic routes to the provision offurther compounds of the invention. Such variations may include, but arenot limited to, the use of appropriate starting materials to generatedifferent compounds, changes in the solvent and temperature ofreactions, replacements of reagents with analogous chemicals,introduction or removal of protection/deprotection stages of functionalgroups sensitive to reaction conditions and reagents, as well asintroduction or removal of specific synthetic steps oriented to furtherfunctionalization of the chemical scaffold.

Compounds used as starting materials or intermediates may becommercially available, their preparation may be specifically describedin the literature or they may be prepared according to known methods.

The process described is particularly advantageous as it is susceptibleof being properly modulated, through any proper known variant, so as toobtain any of the desired compounds. Such variants are comprised withinthe scope of the present invention.

From all of the above, it should be clear to the skilled person that anyof the described groups may be present as such or in any properlyprotected form.

In particular, functional groups present in the Intermediates andExamples and which could generate unwanted side reaction andby-products, need to be properly protected before the alkylation,acylation, coupling or sulfonylation takes place. Likewise, subsequentdeprotection of those same protected groups may follow upon completionof the said reactions.

In the present invention, unless otherwise indicated, the term“protecting group” designates a protective group adapted to preserve thefunction of the group it is bound to. Typically, protective groups areused to preserve amino, hydroxyl, or carboxyl functions. Appropriateprotecting groups may thus include, for example, benzyl,benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters or the like,which are well known [see, for a general reference, T. W. Green;Protective Groups in Organic Synthesis (Wiley, N.Y. 1981), which isincorporated herein by reference in its entirety].

Likewise, selective protection and deprotection of any of the saidgroups, for instance including carbonyl, hydroxyl or amino groups, maybe accomplished according to well known methods.

Optional salification of the compounds of formula (I) may be carried outby properly converting any of the free acidic or amino groups into thecorresponding pharmaceutically acceptable salts. In this case too, theoperative conditions being employed for the optional salification of thecompounds of the invention are all within the ordinary knowledge of theskilled person.

The diastereoisomers of compounds of formula (I), where available, maybe obtained according to methods well known in the art, such as forexample by preparative HPLC or by chromatographic purifications. Aracemic mixture of compounds of formula (I) may as well be separatedusing preparative HPLC and a column with a chiral stationary phase, orresolved to yield individual enantiomers using methods well known in theart. Furthermore, chiral intermediates may be resolved and used toprepare chiral compounds of the invention.

From all of the above, it should be clear to the skilled person that theabove process, comprehensive of any variant thereof for the preparationof suitable compounds of the invention, may be conveniently modified sothat to adapt the reaction conditions to the specific needs, forinstance by choosing appropriate condensing agents, solvents andprotective groups, as the case may be.

Furthermore, compounds of formula (Id), i.e. compounds of formula (I)wherein R₁₄ is a group —COXR₃ and R₁, R₂ are hydrogen and A is CH, maybe prepared according to Scheme D here below reported:

Compounds of formula (XII) can be prepared from compounds of formula(VIII) using the methods described for the synthesis of compounds (Ia)in Scheme A and Scheme B. Compounds of formula (XI) may be prepared fromcompounds of formula (XII) by cleavage of the benzyl ester using anappropriate method such as reduction with a catalyst such as palladiumon carbon in a solvent such as IMS under an atmosphere of hydrogen.Compounds of formula (Id) may be prepared from compounds of formula (XI)by reaction with an alcohol or amine XHR₃ such as ammonia or2-methoxy-ethanol in the presence of a coupling agent such as HATU in asolvent such as DMF in the presence of a base such as triethylamine at atemperature of from room temperature to 80° C.

The synthetic route shown in Scheme C would be of benefit in introducingXR₃ substituents at a late stage.

Alternatively, the acid intermediate (XI) may be prepared from compoundsof formula (Ic) which are compounds of formula (I) wherein X is oxygen,R₃ is methyl, A, R₂ and R₁ are hydrogen, according to Scheme D below:

Treatment of a compound of formula (Ic) where XR₃ is OMe with a strongLewis acid such as boron tribromide in a solvent such as DCM at atemperature of from −78° C. to room temperature followed by quenchingwith water or methanol can provide compounds of formula (XI).

It should be clear to the skilled person that other appropriateprotecting group strategies may be contemplated and that the acid (XI)represents a versatile intermediate for further functionalization aswell as compounds of formula (Id).

By way of example, according to Scheme C1, by appropriate derivatizationof a compound of formula (XI), as above defined, into a compound offormula (XVII) wherein R₁ is not hydrogen, corresponding compounds offormula (Ih) wherein R₁ is not hydrogen may be obtained.

Compounds of formula (XVII) may be obtained from compounds of formula(XI) using the methods described for the transformation of compounds offormula (Ia) to compounds of formula (Ib) in Scheme E. Compounds offormula (Ih) may be prepared from compounds of formula (XVII) using themethods described for the conversion of compounds of formula (XI) tocompounds of formula (Id) in Scheme C.

Compounds of formula (Ib) as above defined may be prepared fromcompounds of formula (Ia) as above defined according to alternativemethods described in Scheme E below.

Compounds of formula (Ia) may be transformed into compounds of formula(Ib) wherein R₁ is an methylene-linked side-chain by reaction with analkyl halide R₁—X′ in the presence of a base such as cesium carbonate ina solvent such as DMF at a temperature of from room temperature to 80°C.

Alternatively, the transformation may be achieved by Mitsunobu reactionwith an alcohol R₁OH. Typical reagents employed are triphenyl phosphineand DIAD in a solvent such as THF.

Where R₁=Aryl or heteroaryl a similar transformation may be achieved bythe use of a Chan-Lam coupling reaction. Typical reaction conditionsconsist of the use of a boronic acid derivative, a copper catalyst suchas copper acetate, a base such as triethylamine and a solvent such aspyridine at a temperature of from room temperature to reflux.

Compounds of formula (Ie), i.e. compounds of formula (I) wherein R₁₄ isa COXR₃ group and R₂ is a group —SO₂Me, may be prepared from compoundsof formula (XVIII) according to Scheme F below:

The transformation may be achieved by reaction of an aryl bromide withsodium methane sulfinite in the presence of a catalyst such as coppertriflate, a ligand such as trans-cyclohexanediamine in a solvent such asDMSO at a temperature of up to 150° C.

Compounds of formula (If) or (Ig), i.e. compounds of formula (I) whichincorporate a group (C₁-C₄)alkyleneNR_(9/7)R_(10/8) or a group(C₁-C₄)alkyleneN⁺R_(11/15)R_(12/16)R_(13/17) respectively assubstituents, may be prepared according to Scheme G.

Compounds of formula (Ig) can be obtained directly by alkylationreaction of an appropriate tertiary amine R_(11/15)R_(12/16)R_(13/17)N,such as trimethylamine or dimethylpiperazine, with compounds of formula(XIX), wherein X′ is an appropriate leaving group (X′═Cl, Br, I,Tosylate etc.) and group —CH₂R represents the portion of a compound offormula (Ig) remaining out of its substitution by a group(C₁-C₄)alkyleneN^(+R) _(11/15)R_(12/16)R_(13/17).

Typical conditions could involve heating a tertiary amine in a solventsuch as ethanol or THF at elevated temperatures of between 60° C. and150° C., using microwave irradiation.

Alternatively, the transformation of compounds of formula (XIX) tocompounds of formula (Ig) may be achieved via the tertiary amine (If)where R_(9/7) and R_(10/8)≠H. Tertiary amine compounds of formula (Ig)may be prepared from compounds of formula (XIX) by reaction with asecondary amine R_(9/7)R_(10/8)NH. Typical reaction conditions includethe use of a base such as cesium carbonate or potassium carbonate in asolvent such as DMF at RT. The conversion of compounds of formula (If),where R_(9/7) and R_(10/8) H, to compounds of formula (Ig) can beobtained using methylating agents such as methyl bromide, methyl iodideor methyl benzenesulfonate. Typical reaction conditions consist of theuse of a solvent such as MeCN or acetone at a temperature of between RTto 60° C. under conventional or microwave heating.

Furthermore, primary and secondary amine compounds of formula (If) mayalso be prepared from compounds of formula (XIX) by reaction withammonia or a suitable primary amine R_(9/7)NH₂, respectively to give aprimary amine or secondary amine.

Compounds of formula (Ij), i.e. compounds of formula (I) wherein R₁₄ isa group —CN, may be prepared according to Scheme H from compounds offormula (Ih), which are compounds of formula (I) wherein XR₃ is NH₂, byreaction with a dehydrating agent such as Burgess reagent in a solventsuch as THF at a temperature of from room temperature to reflux.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES General Experimental Details.

Reactions were not carried out under an inert atmosphere unlessspecified. Where products were purified using an Isolute® SPE Si IIcartridge, ‘Isolute SPE Si cartridge’ refers to a pre-packedpolypropylene column containing unbonded activated silica with irregularparticles with average size of 50 μm and nominal 60 Å porosity. Where anIsolute® SCX-2 cartridge was used, ‘Isolute® SCX-2 cartridge’ refers toa pre-packed polypropylene column containing a non end-cappedpropylsulphonic acid functionalized silica strong cation exchangesorbent. ‘Isolute® PE-AX cartridge’ refers to a pre-packed polypropylenecolumn containing a silica-based sorbent with a chemically bondedquaternary ammonium functional group. All solvents and commercialreagents were used as received.

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probe.Chemical shifts are expressed in ppm relative to tetramethylsilane. Thefollowing abbreviations have been used: br=broad signal, s=singlet,d=doublet, dd=double doublet, t=triplet, td=triplet of doublets,q=quartet, m=multiplet.

Microwave experiments were carried out using a Biotage Initiator 60™which uses a single-mode resonator and dynamic field tuning. Temperaturefrom 40-250° C. can be achieved, and pressures of up to 30 bar can bereached.

Compound names were generated using the Autonom 2000 feature in MDLISIS™/Draw 2.5 SP2 software.

Preparative HPLC Conditions. HPLC System 1.

C18-reverse-phase end-capped column (250×21.2 mm Gemini column with 5 μmparticle size), eluting with a gradient of A: water; B: acetonitrile(0.1% formic acid added) with a flow rate typically 18 mL/min andgradient of 1%/min increasing in B. UV detection at 254 nm.

HPLC System 2.

C18-reverse-phase end-capped column (250×21.2 mm Gemini column with 5 μmparticle size), eluting with a gradient of A: water; B: methanol (0.1%formic acid added) with a flow rate typically 13 mL/min and gradient of1%/min increasing in B. UV detection at 254 nm.

Analytical LC-MS Conditions. LC-MS Method 1.

Waters Platform LC with a C18-reverse-phase column (30×4.6 mm PhenomenexLuna 3 μm particle size), elution with A: water+0.1% formic acid; B:acetonitrile+0.1% formic acid. Gradient:

Gradient-Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 595 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV

MS ionisation method—Electrospray (positive and negative ion)

LC-MS Method 2.

Waters Micromass ZMD with a C18-reverse-phase column (30×4.6 mmPhenomenex Luna 3 μm particle size), elution with A: water+0.1% formicacid; B: acetonitrile+0.1% formic acid. Gradient:

Gradient-Time flow mL/min % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 595 5.50 2.0 5 95 6.00 2.0 95 5Detection—MS, ELS, UV (100 μl split to MS with in-line UV detector)MS ionisation method—Electrospray (positive and negative ion)

LC-MS Method 3.

Waters Micromass ZQ2000 with a C18-reverse-phase column (100×2.1 mmAcquity BEH with 1.7 μm particle size) maintained at 40° C., elutionwith A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid.Gradient:

Gradient-Time flow mL/min % A % B 0.00 0.4 95 5 0.40 0.4 95 5 6.00 0.4 595 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95 5

Detection—MS, UV PDA

MS ionisation method—Electrospray (positive/negative ion)

LC-MS Method 4.

HP1100 with a C18-reverse-phase column (30×4.6 mm Phenomenex Luna 3 μmparticle size), elution with A: water+0.1% formic acid; B:acetonitrile+0.1% formic acid. Gradient:

Gradient-Time flow mL/min % A % B 0.00 2.0 95 5 0.30 2.0 95 5 4.30 2.0 595 5.30 2.0 5 95 5.80 2.0 95 5 6.00 2.0 95 5Detection—MS, ELS, UV (200 μl split to MS with in-line UV detector)MS ionisation method—Electrospray (positive and negative ion)

MDAP System:

Instrumentation: Agilent 1260 infinity purifications system. Agilent6100 series single Quadrupole LC/MS

Column: XSEELECT CSH Prep C18 5 μm OBD, 30×150 mm, RT

Mobile Phase A: 0.1% aqueous formic acidMobile Phase B: 0.1% formic acid in acetonitrileFlow: 60 ml/minGradient Program: 10%-95%, 22 min, centred around a specific focusedgradientSample Injection of a 20-60 mg/ml solution in DMSO (+optional formicacid and water).

Abbreviations Used in the Experimental Section:

-   BBr₃ Boron tribromide-   CH₃CN Acetonitrile-   DCM Dichloromethane-   DIAD Di-isopropyl azodicarboxylate-   DIPEA Di-isopropylethylamine-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   Et₃N Triethylamine-   EtOAC Ethyl acetate-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   IMS Industrial methylated spirits-   LC-MS Liquid chromatography-mass spectrometry-   mCPBA 3-Chloroperbenzoic acid-   MDAP Mass-directed automated HPLC purification-   MeOH Methanol-   mins Minutes-   mL Millilitre-   Mmol Millimol-   N₂ Nitrogen-   Na₂SO₄ Sodium sulfate-   Na₂S₂O₃Sodium thiosulphate-   RT Room temperature-   Rt Retention time-   TBAF Tetrabutylammonium fluoride-   THF Tetrahydrofuran

In the procedures that follow, some of the starting materials areidentified through an “Intermediate” or “Example” number. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

When reference is made to the use of a “similar” or “analogous”procedure, as will be appreciated by those skilled in the art, such aprocedure may involve minor variations, for example reactiontemperature, reagent/solvent amount, reaction time, work-up conditionsor chromatographic purification conditions.

Intermediate 1.4-(4-Cyanophenyl)-6-methyl-2-thioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid methyl ester

To a solution of 3-trifluoromethylphenylthiourea (2.2 g, 10 mmol)4-cyanobenzaldehyde (1.4 g, 11 mmol) and methyl acetoacetate (1.2 mL, 11mmol) in THF (40 mL) was added trimethylsilylphosphate (1.8 g) and themixture heated at 70° C. After 17 hours, the reaction mixture wasallowed to cool, then poured onto 0.5 M HCl (200 mL) and extracted intoEtOAc. The organic phase was washed with water, then brine, dried(Na₂SO₄) and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography eluting with a gradient of 20-30% EtOAc incyclohexane Appropriate fractions were combined and concentrated invacuo to yield the title compound as a white foam (3.7 g).

LC-MS (Method 1): Rt=3.88 min, m/z=432 [M+H]⁺

Intermediate 2.4-(4-Cyanophenyl)-2-hydrazino-6-methyl-1-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

To a solution of intermediate 1 (2 g, 4.6 mmol) in IMS (100 mL) wasadded urea hydrogen peroxide (865 mg, 9.2 mmol) and the mixture wasstirred for 5 hours at RT before addition of hydrazine hydrate (891 μL,18.4 mmol). The reaction mixture was stirred for a further 16 hours atRT and then the solvent reduced to a low volume in vacuo. The resultantresidue was partitioned between EtOAc and saturated aqueous Na₂S₂O₃. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with 80% EtOAc in cyclohexane. Appropriatefractions were combined and concentrated in vacuo to yield the titlecompound as a yellow oil (729 mg).

LC-MS (Method 2): Rt=2.38 min, m/z=430 [M+H]⁺

Intermediate 3.4-(4-Cyanophenyl)-2-(N′-methoxycarbonyl-hydrazino)-6-methyl-1-(3-trifluoromethylphenyl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Intermediate 2 (724 mg, 1.7 mmol) was dissolved in THF (20 mL) andcooled to 0° C. before addition of triethylamine (362 μl, 2.6 mmol) andethyl chloroformate (191 μL, 2 mmol). The reaction mixture was stirredat 0° C. for 1 hour and then partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resultant residue was triturated with EtOAc,filtered and the solid collected to yield the title compound as a whitesolid (49 mg).

LC-MS (Method 2): Rt=2.47 min, m/z=502 [M+H]⁺

Intermediate 4.4-(4-Cyanophenyl)-2-methoxy-6-methyl-1,4-dihydropyrimidine-5-carboxylicacid methyl ester

To a solution of 4-cyanobenzaldehyde (13.1 g, 100 mmol) in DMF (200 mL),was added sodium bicarbonate (33.4 g, 400 mmol), followed byO-methylisourea hemisulphate (14.8 g, 120 mmol) and methyl acetoacetate(12.8 g, 110 mmol). The reaction mixture was heated at 70° C. for 5hours, then poured into water and the product was extracted into EtOAc.The organic phase was washed with water (×2) followed by brine thendried (Na₂SO₄) and evaporated to dryness. The resulting yellow gum waspurified by silica gel chromatography eluting with diethyl ether to givethe title compound as a yellow solid (12.8 g).

LC-MS (Method 1): Rt=2.20 min, m/z=286 [M+H]⁺

Intermediate 5.6-(4-Cyanophenyl)-2-methoxy-4-methyl-6H-pyrimidine-1,5-dicarboxylic acid5-methyl ester 1-(4-nitrophenyl)ester

Intermediate 4 (1.56 g, 5.46 mmol) was dissolved in a mixture of DCM (25mL) and pyridine (10 mL) and cooled using an ice bath. A solution of4-nitrophenyl chloroformate (705 mg, 3.50 mmol) in DCM (25 mL) was addedover 30 minutes. The reaction mixture was stirred for 1 hour at 0° C.and then the solvent was removed in vacuo. The resulting residue waspurified by silica gel chromatography eluting with a gradient of 0-20%EtOAc in cyclohexane to gave the title compound as a yellow solid. Theproduct thus obtained was used in the subsequent step without furtheranalysis (2.0 g).

Intermediate 6.2-Benzyl-5-(4-cyanophenyl)-7-methyl-3-oxo-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 5 (250 mg, 0.55 mmol) and benzyl hydrazine hydrochloride(120 mg, 0.61 mmol) were suspended in CH₃CN (10 mL) at 0° C., and Et₃N(85 μl, 0.61 mmol) was added. The reaction mixture was stirred at 0° C.for 30 mins and then allowed to reach RT and stirred for a further 1hour. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The resulting residue was purified by silica gelchromatography eluting with a gradient of 0-100% to yield the titlecompound as a yellow solid (100 mg).

LC-MS (Method 2): Rt=3.87 min, m/z=402 [M+H]⁺

Intermediate 7.2-Allyl-5-(4-cyanophenyl)-7-methyl-3-oxo-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 4 (1.42 g, 5 mmol) was dissolved in a mixture of DCM (10mL) and pyridine (10 mL) and cooled using an ice bath. A solution of4-nitrophenyl chloroformate (0.955 mg, 4.75 mmol) in DCM (10 mL) wasadded dropwise, and the resulting solution was stirred at 0° C. for 1.5hours, and then a solution of allyl hydrazine hydrochloride (1.0 g, 5.5mmol) and DIPEA (3.75 mL, 22 mmol) in CH₃CN (10 mL) was added in oneportion. The resulting mixture was allowed to warm to RT, stirred for 4hours, and then partitioned between EtOAc and water. The organic layerwas separated, washed with water, followed by brine, then dried (Na₂SO₄)and evaporated in vacuo to yield the title compound as a yellow oil(0.95 g).

LC-MS (Method 2): Rt=2.73 min, m/z=352 [M+H]⁺

Intermediate 8.5-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 8 was prepared using an analogous method to that describedabove for Intermediate 7.

LC-MS (Method 2): Rt=2.46 min, m/z=326 [M+H]⁺

Intermediate 9.(R)-4-(4-Cyanophenyl)-6-methyl-2-thioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid methyl ester

To a solution of(R)-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylicacid methyl ester (14.5 g, 35 mmol) (prepared according to WO2006/082412, which is incorporated herein by reference in its entirety)in toluene (105 mL) under an atmosphere of N₂, was added Lawesson'sreagent (17 g, 42 mmol), and the resulting mixture stirred at 120° C.for 17 hours. The reaction mixture was allowed to cool to RT and thenevaporated in vacuo. The resulting residue was dissolved in diethylether, filtered, and the filtrate collected, washed with brine, dried(Na₂SO₄) and evaporated in vacuo. The resulting residue was purified bysilica gel chromatography eluting with a gradient of 10-40% EtOAc incyclohexane to yield the title compound as a yellow foam (4.8 g).

LC-MS (Method 2): Rt=3.75 min, m/z=432 [M+H]⁺

Intermediate 10.(R)-4-(4-Cyanophenyl)-2-hydrazino-6-methyl-1-(3-trifluoromethylphenyl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Intermediate 10 (593 mg) was prepared from Intermediate 9 (3.39, 7.9mmol) according to an analogous procedure to that described forIntermediate 2.

LC-MS (Method 1): Rt=2.57 min, m/z=430 [M+H]⁺

Intermediate 11.(R)-4-(4-Cyanophenyl)-2-(N′-methoxycarbonyl-hydrazino)-6-methyl-1-(3-trifluoromethylphenyl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Intermediate 11 (381 mg) was prepared from Intermediate 10 (782 mg, 1.8mmol) according to an analogous procedure to that described forIntermediate 3.

LC-MS (Method 1): Rt=2.60 min, m/z=502 [M+H]⁺

Intermediate 12.5-(2-Bromo-4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 12 (2.58 g) was prepared according to analogous proceduresto those described for Intermediates 1, 2, and 3 and Example 1, using2-bromo-4-cyanobenzaldehyde (12 g, 57 mmol) in place of4-cyanobenzaldehyde as starting material of the synthetic sequence.

LC-MS (Method 3): Rt=4.65 min, m/z=534 [M(⁷⁹Br)+H]⁺

¹H NMR (400 MHz, DMSO) δ 11.20 (1H, s), 8.18 (1H, d, J=1.6 Hz), 8/0991H, br s), 7.93-7.75 (5H, m), 6.23 (1H, d, J=1.2 Hz), 3.49 (3H, s),2.13 (3H, s).

Intermediate 13.5-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid amide

Example 9 (160 mg, 0.36 mmol) was dissolved in DMF (5 mL) and thendiiosopropylethylamine (123 μL, 0.72 mmol) was added followed by HATU(280 mg, 0.72 mmol). After 1 hour, ammonia (0.5 M in dioxane, 4.3 mL,2.15 mmol) was added, and the mixture stirred at 60° C. for 16 hours.The mixture was allowed to cool to RT, then partitioned between EtOAcand water. The organic layer was separated, and the aqueous layerextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄) and evaporated in vacuo. The resulting residue waspurified by silica gel chromatography eluting with a gradient of 0-10%MeOH in DCM to yield the title compound as a white solid (120 mg).

LC-MS (Method 3): Rt=3.47 min, m/z=440 [M+H]⁺

Intermediate 14. 1-Bromo-3-methanesulfonyl-propane

To a solution of 3-(methylsulfonyl)-1-propanol (276 mg, 2 mmol) in DCM(10 mL), was added carbon tetrabromide (730 mg, 2.2 mmol) followed byportion-wise addition of triphenylphosphine (580 mg, 2.2 mmol) under anatmosphere of N₂. The resulting solution was stirred at RT for 17 hours.The reaction mixture was partitioned between DCM and water. The organiclayer was separated, washed with brine, dried (Na₂SO₄) and evaporated invacuo. The resulting residue was purified by silica gel chromatographyusing eluting with 50% EtOAc in cyclohexane to give the title compoundas a colourless oil (297 mg).

¹H NMR (400 MHz, DMSO) δ 3.63 (2H, t J=7 Hz), 3.25-3.20 (2H, m), 3.01(3H, s), 2.27-2.19 (2H, m)

Intermediate 15.2-(4-Bromomethyl-benzyl)-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (228 mg, 0.5 mmol) was dissolved in DMF (5 mL), and cesiumcarbonate (652 mg, 2 mmol) and α,α′-dibromo-p-xylene (396 mg, 1.5 mmol)were added. The reaction mixture was stirred at RT for 1 hour and wasthen partitioned between

EtOAc and water. The organic layer was separated, washed with brine,dried (Na₂SO₄) and evaporated in vacuo. The resulting residue waspurified by silica gel chromatography eluting with 40% EtOAc incyclohexane as eluent to give the title compound as a white solid (211mg).

LC-MS (Method 4): Rt=4.11 min, m/z 638 [M(⁷⁹Br)+H]⁺

Intermediate 16.5-(4-Cyano-phenyl)-2-methoxycarbonylmethyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (108 mg, 0.24 mmol) was dissolved in DMF (2 mL), and cesiumcarbonate (94 mg, 0.29 mmol) and methyl bromoacetate (24 μL, 0.26 mmol)were added. The reaction mixture was stirred at RT for 2 hours and thenpartitioned between EtOAc and water. The organic layer was separated,and the aqueous layer further extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo.The resulting residue was purified by silica gel chromatography elutingwith a gradient of 0-30% EtOAc in DCM and to yield the title compound asa white solid (112 mg).

LC-MS (Method 2): Rt=3.59 min, m/z=528 [M+H]⁺

Intermediate 17.2-Carboxymethyl-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

To a solution of Intermediate 16 (108 mg, 0.21 mmol) in THF (1 mL), wasadded MeOH (1 mL) followed by lithium hydroxide (3 M in water, 68 μL,0.21 mmol). The reaction mixture was stirred at RT for 2 hours, and thenlithium hyroxide (3 M in water, 27 μL, 0.08 mmol) was added. After afurther 1 hour stirring at RT, the reaction mixture was made acidic byaddition of 1 M HCl and extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo toyield the title compound as a white solid (100 mg).

LC-MS (Method 2): Rt=3.33 min, m/z=514 [M+H]⁺

Intermediate 18.2-[3-(tert-Butoxycarbonyl-methyl-amino)-propyl]-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (0.2 g, 0.44 mmol) was dissolved in DMF (4 mL), and cesiumcarbonate (0.19 g, 0.53 mmol) was added, followed by(3-iodo-propyl)-methyl-carbamic acid tert-butyl ester (0.14 g, 0.48mmol). The reaction mixture was stirred at RT for 18 hours and thenquenched with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo.The resulting residue was purified by silica gel chromatography elutingwith a gradient of 0-5% MeOH in DCM to yield the title compound as awhite solid (238 mg).

LC-MS (Method 2): Rt=4.02 min, m/z=627 [M+H]⁺

Intermediate 19.3-[3-(tert-Butyl-dimethyl-silanyloxy)-propylsulfanyl]-propan-1-ol

A solution of 3,3′-thiodipropanol (900 mg, 6 mmol) in THF (3 ml) wasadded dropwise to a suspension of sodium hydride (240 mg, 6 mmol) in THF(15 ml) under an atmosphere of N₂. The reaction mixture was stirred atRT for 30 mins, then a solution of tert-butyldimethylsilylchloride (900mg, 6 mmol) in THF (2 ml) was added and stirring was continued for 16hours. The reaction mixture was partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with 20% EtOAc in cyclohexane to give the titlecompound as a colourless oil (793 mg).

¹H NMR (400 MHz, DMSO) 4.44-4.30 (1H, m), 3.71-3.63 (2H, m), 3.52-3.43(2H, m), 3.29-3.18 (4H, m), 1.76-1.63 (4H, m), 0.89 (9H, s), 0.06 (6H,s).

Intermediate 20.3-[3-(tert-Butyl-dimethyl-silanyloxy)-propane-1-sulfonyl]-propan-1-ol

Intermediate 19 (782 mg, 2.96 mmol) was dissolved in DCM (25 ml), andmCPBA (1.55 g, 9 mmol) was added. The reaction mixture was stirred at RTfor 2 hours and then partitioned between DCM and saturated aqueousNa₂S₂O₅. The organic layer was separated, washed with saturated aqueousNaHCO₃, then brine, dried (Na₂SO₄) and evaporated in vacuo to yield thetitle compound as a white solid (919 mg).

¹H NMR (400 MHz, DMSO) δ 4.69 (1H, s), 3.73-3.66 (2H, m), 3.53-3.48 (2H,m), 3.16-3.08 (4H, m), 1.91-1.78 (4H, m), 0.89 ((H, s), 0.07 (6H, s).

Intermediate 21.2-{3-[3-(tert-Butyl-dimethyl-silanyloxy)-propane-1-sulfonyl]-propyl}-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (228 mg, 0.5 mmol) was dissolved in THF (5 mL), and thenIntermediate 20 (178 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6mmol) were added followed by dropwise addition of a solution ofdiisopropyl azodicarboxylate (118 μL, 0.6 mmol) in THF (1 ml). Thereaction mixture was stirred at RT for 5 hours and then partitionedbetween EtOAc and water. The organic layer was separated, and theaqueous layer further extracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresulting residue was purified by silica gel chromatography eluting with50% EtOAc in cyclohexane to afford the title compound (282 mg).

LC-MS (Method 2): Rt=4.49 min, m/z=734 [M+H]⁺

Intermediate 22.5-(4-Cyano-phenyl)-2-[3-(3-hydroxy-propane-1-sulfonyl)-propyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 21 (282 mg, 0.38 mmol) was dissolved in THF (3 mL), andthen a solution of 1 M TBAF in THF (760 μl, 0.76 mmol) was added. Thereaction mixture was stirred at RT for 4 hours and then partitionedbetween EtOAc and water. The organic layer was separated, and theaqueous layer further extracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresulting residue was purified by silica gel chromatography eluting witha gradient of 0-2% methanol in EtOAc to afford the title compound (89mg).

LC-MS (Method 2): Rt=3.29 min, m/z=620 [M+H]⁺

Intermediate 23.5-(4-Cyano-phenyl)-7-methyl-3-oxo-2-{3-[3-(toluene-4-sulfonyloxy)-propane-1-sulfonyl]-propyl}-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 22 (89 mg, 0.14 mmol) was dissolved in THF (3 ml), and thensodium hydride (6 mg, 0.2 mmol) was added under an atmosphere of N₂. Thereaction mixture was stirred at RT for 10 mins, then toluenesulfonylchloride (31 mg, 0.16 mmol) was added and stirring was continued for 16hours. The reaction mixture was partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluing with a gradient of 50-80% EtOAc in cyclohexane toyield the title compound as a colourless oil (70 mg).

LC-MS (Method 4): Rt=3.81 min, m/z=774 [M+H]⁺

Intermediate 24.[3-(3-Bromo-propane-1-sulfonyl)-propoxy]-tert-butyl-dimethyl-silane

Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4mmol)) according to an analogous procedure to that described forIntermediate 14.

¹H NMR (400 MHz, DMSO) 3.68 (2H, t, J=6 Hz), 3.63 (2H, t, J=6 Hz),3.25-3.21 (2H, m), 3.16-3.11 (2H, m), 2.26-2.17 (2H, m), 1.90-1.82 (2H,m), 0.87 (9H, s), 0.05 (6H, s).

Intermediate 25.(R)-5-(4-Cyano-phenyl)-2-methoxycarbonylmethyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 7 (227 mg, 0.5 mmol) was dissolved in DMF (4 mL), and cesiumcarbonate (195 mg, 0.6 mmol) and methyl bromoacetate (51 μL, 0.55 mmol)were added. The reaction mixture was stirred at RT for 18 hours and thenpartitioned between EtOAc and water. The organic layer was separated,and the aqueous layer further extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo.The resulting residue was purified by silica gel chromatography elutingwith 50% EtOAc in cyclohexane to yield the title compound as acolourless glass (244 mg).

LC-MS (Method 4): Rt=3.16 min, m/z=528 [M+H]⁺

Intermediate 26.(R)-2-Carboxymethyl-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

To a solution of Intermediate 25 (240 mg, 0.46 mmol) in THF (3 mL), wasadded MeOH (3 mL) followed by lithium hydroxide (3M in water, 200 μL,0.6 mmol). The reaction mixture was stirred at RT for 2 hours, and thenthe volatiles were removed in vacuo. The resultant residue was dissolvedin water, and the solution thus obtained was made acidic by addition of6 N HCl and extracted with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄) and evaporated in vacuo to yield thetitle compound as a colourless oil (250 mg).

LC-MS (Method 4): Rt=2.88 min, m/z=514 [M+H]⁺

Intermediate 27.(R)-2-{3-[3-(tert-Butyl-dimethyl-silanyloxy)-propane-1-sulfonyl]-propyl}-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 7 (455 mg, 1 mmol) was dissolved in DMF (5 mL), and cesiumcarbonate (489 mg, 1.5 mmol) and a solution of Intermediate 24 (481 mg,1.3 mmol) were added. The reaction mixture was stirred at RT for 16hours and then partitioned between EtOAc and water. The organic layerwas separated, and the aqueous layer further extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with 50% EtOAc in cyclohexane to yield the titlecompound as an off-white foam (623 mg).

LC-MS (Method 2): Rt=7.33 min, m/z=734 [M+H]⁺

Intermediate 28.(R)-5-(4-Cyano-phenyl)-2-[3-(3-hydroxy-propane-1-sulfonyl)-propyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 27 (620 mg, 0.85 mmol) was dissolved in THF (7 mL), andthen a solution of 1 M TBAF in THF (1.3 ml, 1.3 mmol) was added. Thereaction mixture was stirred at RT for 16 hours and then partitionedbetween EtOAc and water. The organic layer was separated, and theaqueous layer further extracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresulting residue was purified by silica gel chromatography eluting witha gradient of 4-5% methanol in DCM to afford the title compound as acolourless oil (476 mg).

LC-MS (Method 4): Rt=2.83 min, m/z=620 [M+H]⁺

Intermediate 29.(R)-5-(4-Cyano-phenyl)-7-methyl-3-oxo-2-{3-[3-(toluene-4-sulfonyloxy)-propane-1-sulfonyl]-propyl}-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 28 (470 mg, 0.76 mmol) was dissolved in THF (5 ml), andthen sodium hydride (48 mg, 1.2 mmol) was added under an atmosphere ofN₂. The reaction mixture was stirred at RT for 10 mins, thentoluenesulfonyl chloride (191 mg, 1 mmol) was added and stirring wascontinued for 16 hours. The reaction mixture was partitioned betweenEtOAc and water. The organic layer was separated, washed with brine,dried (Na₂SO₄) and evaporated in vacuo. The resulting residue waspurified by silica gel chromatography eluing with a gradient of 50-80%EtOAc in cyclohexane to give the title compound as a pale yellow glass(132 mg).

LC-MS (Method 4): Rt=3.43 min, m/z=774 [M+H]⁺

Example 15-(4-Cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 3 (400 mg, 0.8 mmol) was dissolved in IMS (12 mL) andheated at 150° C. for 1 hour using microwave irradiation. The solventwas removed in vacuo, and the resulting residue was purified by silicagel chromatography eluing with a gradient of 50-70% EtOAc in cyclohexaneto yield the title compound as a white solid (185 mg).

LC-MS (Method 2): Rt=3.32 min, m/z=456 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 11.25 (1H, s), 8.09 (1H, s), 7.93-7.78 (5H, m),7.67 (2H, d, J=8 Hz), 5.92 (1H, s), 3.55 (3H, s) and 2.16 (3H, s).

Example 22-Carbamoylmethyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (85 mg, 0.19 mmol) was dissolved in DMF (3 mL), and cesiumcarbonate (94 mg, 0.29 mmol) and 2-iodoacetamide (41 mg, 0.22 mmol) wereadded. The reaction mixture was stirred at RT for 3 hours and thenpartitioned between EtOAc and water. The organic layer was separated,washed with brine, dried (Na₂SO₄) and evaporated in vacuo. The resultingresidue was purified by silica gel chromatography eluting with EtOAc togive the title compound as a pale yellow solid (49 mg).

LC-MS (Method 3): Rt=4.14 min, m/z=513 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.08 (1H, s), 7.93-7.79 (5H, m), 7.70 (2H, d,J=8 Hz), 7.26 (1H, s), 7.12 (1H, s), 5.96 (1H, s), 4.07 (1H, d, J=17Hz), 3.98 (1H, d, J=17 Hz), 3.56 (3H, s), and 2.15 (3H, s).

Example 35-(4-Cyanophenyl)-2-(2-dimethylamino-propyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (85 mg, 0.19 mmol) was dissolved in DMF (3 mL), and cesiumcarbonate (156 mg, 0.48 mmol) and 3-dimethylamin-1-propylchloridehydrochloride (35 mg, 0.22 mmol) were added. The reaction mixture wasstirred at RT for 16 hours and then heated at 65° C. for 3 hours. Thereaction mixture was allowed to cool and then partitioned between EtOAcand water. The organic layer was separated, washed with brine, dried(Na₂SO₄) and evaporated in vacuo. The resulting residue was purified bysilica gel chromatography eluting with a gradient of 4-10% MeOH in DCMto yield the title compound as an off-white solid (23 mg).

LC-MS (Method 3): Rt=3.53 min, m/z=541 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.10 (1H, s), 7.94-7.79 (5H, m), 7.67 (2H, d,J=8 Hz), 5.95 (1H, s), 3.55 (3H, s), 3.52-3.39 (2H, m), 2.15 (3H, s),2.03 (2H, td, J=2 and 7 Hz), 1.98 (6H, s) and 1.57-146 (2H, m).

Example 42-Benzyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 6 (100 mg, 0.24 mmol), 3-trifluoromethylphenylboronic acid(95 mg, 0.5 mmol), Et₃N (250 μl, 1.8 mmol), and copper (II) acetate (50mg, 0.4 mmol) were dissolved in DCM (10 mL), and stirring at RT wascontinued for 48 hours. The reaction mixture was filtered to remove thesolid and the filtrate was concentrated in vacuo. The resulting residuewas purified by silica gel chromatography eluting with a gradient of0-15% MeOH in DCM. Appropriate fractions were combined and concentratedin vacuo and the resulting residue further purified using preparativeHPLC system 2 to yield the title compound as a white solid (20 mg).

LC-MS (Method 3): Rt=5.43 min, m/z=546 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.77 (1H, d, J=8 Hz), 7.70-7.65 (3H, m)7.59-7.54 (3H, m), 7.51 (1H, d, J=8 Hz), 7.29-7.24 (3H, m), 7.22-7.18(2H, m), 6.14 (1H, s), 4.80 (1H, d, J=15 Hz), 4.60 (1H, d, J=15 Hz),3.64 (3H, s) and 2.25 (3H, s).

Example 52-Allyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 5 was prepared from Intermediate 7 using an analogous method tothat described above for Example 4 to yield the title compound as awhite powder.

LC-MS (Method 3): Rt=4.10 min, m/z=496 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.11 (1H, s), 7.94-7.89 (2H, m), 7.88-7.79 (3H,m), 7.69 (2H, d, J=8 Hz), 5.96 (1H, s), 5.72-5.62 (1H, m), 5.04 (1H, dd,J=1 and 10 Hz), 4.95 (1H, dd, J=1 and 16 Hz), 4.14-4.04 (2H, m), 3.55(3H, s) and 2.14 (3H, s).

Example 65-(4-Cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 8 (900 mg, 2.77 mmol), 3-trifluoromethylphenylboronic acid(1.05 g, 5.54 mmol), Et₃N (925 μl, 6.6 mmol), and copper (II) acetate(1.0 g, 5.54 mmol) were dissolved in DCE (25 mL), and the reactionmixture was stirred at 80° C. for 18 hours. After cooling to RT thereaction mixture was partitioned between DCM and water. The organiclayer was separated, washed with water, followed by brine, then dried(MgSO₄) and evaporated in vacuo. The resulting residue was purified bysilica gel chromatography eluting with a gradient of 3-10% MeOH in DCMand then using HPLC system 1 to yield the title compound as an orangesolid (47 mg).

LC-MS (Method 3): Rt=4.80 min, m/z=470 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.11 (1H, s), 7.91 (2H, t, J=8 Hz), 7.87-7.79(3H, m), 7.69 (2H, d, J=8 Hz), 5.94 (1H, s), 3.55 (3H, s), 3.08 (3H, s)and 2.15 (3H, s).

Example 7(R)-5-(4-Cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 7 (112 mg) was prepared from Intermediate 11 (376 mg) accordingto an analogous procedure to that described for Example 1.

Alternatively, Example 7 could be made from Example 1 by submittingExample 1 to preparative HPLC chromatography on a chiral phase [DaicelChiralpak IC column (5 μm, 250 mm×10 mm, 3% IPA/DCM eluent, 5 ml/minflow rate, 220 nm detection)]. Example 1 (3.15 g) was dissolved in 3%IPA/DCM (60 ml) and run with 60 injections of 1 ml to give the (R)enantiomer (2nd eluting enantiomer) (1.5 g).

LC-MS (Method 3): Rt=4.42 min, m/z=456 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 11.25 (1H, s), 8.09 (1H, s), 7.93-7.78 (5H, m),7.67 (2H, d, J=8 Hz), 5.92 (1H, s), 3.55 (3H, s) and 2.16 (3H, s).

Example 85-(4-Cyano-phenyl)-2-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (60 mg, 0.13 mmol) was dissolved in DMF (1 mL), and cesiumcarbonate (51 mg, 0.16 mmol) and 2-chloro-N,N-dimethylacetamide (15 μl,0.15 mmol) were added. The reaction mixture was stirred at RT for 16hours and then partitioned between EtOAc and water. The organic layerwas separated, and the aqueous layer further extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with 50% EtOAc in DCM to give the title compoundas a white solid (56 mg).

LC-MS (Method 3): Rt=4.45 min, m/z=549 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.04 (1H, s), 7.87-7.74 (5H, m), 7.64 (2H, d,J=9 Hz), 5.93 (1H, s), 4.36 (2H, s), 3.52 (3H, s), 2.80 (3H, s), 2.68(3H, s), 2.15 (3H, s).

Example 95-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid

Example 1 (100 mg, 0.22 mmol) was dissolved in DCM (2 mL) under anatmosphere of N₂ and cooled to −78° C. before the dropwise addition ofBBr₃ (1M in DCM, 1 mL, 1 mmol). The reaction mixture was stirred at −78°C. for 1 hour, before warming to 0° C. and stirring for a further 4hours. The reaction mixture was cautiously quenched with saturatedaqueous NaHCO₃ and then diluted with DCM. The aqueous layer wasseparated, acidified to pH 1 by addition of 6 N HCl and then extractedwith DCM. The combined extracts were concentrated in vacuo to yield thetitle compound as a white solid (53 mg).

LC-MS (Method 3): Rt=3.81 min, m/z=442 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 12.49 (1H, br s), 11.22 (1H, s), 8.08 (1H, s),7.92-7.77 (5H, m), 7.66 (2H, d, J=8 Hz), 5.90 (1H, s), 2.17 (3H, s).

Example 105-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid 2-dimethylamino-ethyl ester

To a solution of Example 9 (32 mg, 0.073 mmol) in DMF (1 mL), was addeddiiosopropylethylamine (125 μL, 0.73 mmol) followed by HATU (30 mg,0.080 mmol). After 1 hour, N,N-dimethylethanolamine (73 μL, 0.73 mmol)was added, and the reaction mixture was stirred at RT for 16 hours. Thereaction mixture was partitioned between EtOAc and water. The organiclayer was separated, and the aqueous layer further extracted with EtOAc.The combined organic layers were washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by reverse phaseHPLC using a gradient 20-70% acetonitrile in water with 0.1% ammonia toyield the title compound as a white solid (4 mg).

LC-MS (Method 3): Rt=3.14 min, m/z=513 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 8.39 (1H, br s), 7.77 (1H, d, J=8 Hz),7.71-7.53 (7H, m), 6.11 (1H, s), 4.20-4.06 (2H, m), 2.49-2.47 (2H, m),2.26 (3H, s), 2.21 (6H, s).

Example 115-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid 3-dimethylamino-propyl ester

To a solution of Example 9 (42 mg, 0.095 mmol) in DMF (1 mL), was addeddiiosopropylethylamine (33 μL, 0.19 mmol) followed by HATU (72 mg, 0.19mmol). After 1 hour, N,N-dimethylpropanolamine (67 μL, 0.57 mmol) wasadded, and the reaction mixture was stirred at 60° C. for 16 hours. Thereaction mixture was allowed to cool to RT then partitioned betweenEtOAc and water. The organic layer was separated, and the aqueous layerfurther extracted with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄) and evaporated in vacuo. The resultingresidue was purified by silica gel chromatography eluting with agradient of 0-6% (2 M NH₃ in MeOH) in DCM to give the title compound asa white solid (15 mg).

LC-MS (Method 3): Rt=3.18 min, m/z=527 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 9.22 (1H, br s), 7.76 (1H, d, J=7 Hz),7.69-7.61 (3H, m), 7.58-7.51 (4H, m), 6.08 (1H, s), 4.04 (2H, t, J=6),2.25 (3H, s), 2.21 (6H, s), 2.11-2.07 (2H, m), 1.67-1.60 (2H, m).

Example 125-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid ethylamide

To a solution of Example 9 (100 mg, 0.23 mmol) in DMF (3 ml), were addedDIPEA (102 μl, 0.6 mmol) and HATU (133 mg, 0.35 mmol) and the reactionmixture was stirred at RT for 45 mins. Ethylamine (2 M in THF, 175 μL,0.35 mmol) was then added, and stirring at RT was continued for 16hours. Further ethylamine (2 M in THF, 175 μL, 0.35 mmol) was added, thetemperature was raised to 60° C., and stirring was continued for 1.5hours. The reaction mixture was partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with a gradient of 80-100% EtOAc in cyclohexaneto yield the title compound as a white solid (53 mg).

LC-MS (Method 3): Rt=3.84 min, m/z=469 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 11.12 (1H, s), 8.00 (1H, t, J=6 Hz), 7.94 (1H,s), 7.88-0.775 (5H, m), 7.54 (2H, d, J=9 Hz), 5.95 (1H, s), 3.02-2.92(2H, m), 1.78 (3H, s), 0.88 (3H, t, J=7.5 Hz).

Example 135-(4-Cyano-2-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 12 (235 mg, 0.44 mmol) was dissolved in DMSO (4.5 mL) andpurged with N₂ for 5 mins. Sodium methane sulfinite (220 mg, 2.2 mmol)and trans-cyclohexane-1,2-diamine were then added, followed by copper(I)trifluoro-methanesulfonate benzene complex (222 mg, 0.44 mmol). Thereaction mixture was stirred at 120° C. under N₂ for 18 h and thenallowed to cool to RT. The reaction mixture was partitioned betweenEtOAc and water. The organic layer was separated, and the aqueous layerfurther extracted with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄) and evaporated in vacuo. The resultingresidue was purified by reverse phase HPLC using a gradient of 60-90%MeOH in water with 0.1% formic acid to give the title compound as awhite solid (6.5 mg).

LC-MS (Method 3): Rt=4.37 min, m/z=534 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 8.32 (1H, d, J=1 Hz), 7.91 (2H, dd, J=8, 1Hz), 7.82 (1H, d, J=8 Hz), 7.73 (1H, t, J=8), 7.65-7.58 (4H, m), 3.57(3H, s), 3.44 (3H, s), 2.22 (3H, s).

Example 145-(4-Cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile

Intermediate 13 (92 mg, 0.209 mmol) was dissolved in THF (8 mL), andBurgess reagent (150 mg, 0.63 mmol) was added. The reaction mixture wasstirred at RT for 30 mins and was then partitioned between EtOAc andwater. The organic layer was separated, and the aqueous layer furtherextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄) and evaporated in vacuo. The resulting residue waspurified by silica gel chromatography eluting with 80% EtOAc incyclohexane as eluent to yield a white solid. Further purification wascarried out by reverse phase HPLC using a gradient of 40-98% MeCN inwater (+0.1% formic acid) to yield the title compound as a white solid(34 mg).

LC-MS (Method 3): Rt=4.28 min, m/z=423 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 8.07 (1H, s), 7.81 (1H, d, J=8), 7.75-7.69(3H, m), 7.6 (1H, s), 7.54-7.49 (3H, m), 5.68 (1H, s), 2.05 (3H, s).

Example 155-(4-Cyano-phenyl)-2-(4-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (68 mg, 0.15 mmol) was dissolved in DCM (3 mL), and4-methansulfonylphenyl boronic acid (90 mg, 0.45 mmol), copper (II)acetate (54 mg, 0.3 mmol), triethylamine (105 μL, 0.75 mmol), pyridine(48 μL, 0.6 mmol), and powdered 4 Å sieves (100 mg) were added. Thereaction mixture was stirred at RT for 72 hours and was then filtered,and the filtrate collected and evaporated in vacuo. The resultingresidue was purified by silica gel chromatography eluting with agradient of 40-50% EtOAc in cyclohexane and the resulting residue wastriturated with 1:1 EtOAc:MeOH, filtered and the solid collected toyield the title compound as a white solid (7 mg).

LC-MS (Method 3): Rt=5.10 min, m/z=610 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.22 (1H, s), 8.03-7.97 (2H, m), 7.91-7.85 (5H,m), 7.81-7.77 (4H, m), 6.07 (1H, s), 3.57 (3H, s), 3.13 (3H, s), 2.18(3H, s).

Example 165-(4-Cyano-phenyl)-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (68 mg, 0.15 mmol) was dissolved in THF (2 mL) under anatmosphere on N₂, and 3-(methylsulfonyl)-1-propanol (25 mg, 0.18 mmol)and triphenylphosphine (47 mg, 0.18 mmol) were added followed bydropwise addition of DIAD (35 μL, 0.18 mmol) in THF (200 μL). Thereaction mixture was stirred at RT for 5 hours, and then further3-(methylsulfonyl)-1-propanol (25 mg, 0.18 mmol) and triphenylphosphine(47 mg, 0.18 mmol) were added followed by dropwise addition of DIAD (35μL, 0.18 mmol) in THF (200 μL). The reaction mixture was stirred for afurther 16 hours and then partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with a gradient of 50-100% EtOAc to give thetitle compound as a white solid (55 mg).

LC-MS (Method 3): Rt=4.50 min, m/z=576 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.12 (1H, s), 7.92 (2H, dd, J=1 Hz and 7.5 Hz),7.87-7.79 (3H, m), 7.69 (2H, d, J=7.5 Hz), 5.96 (1H, s), 3.68-3.60 (1H,m), 3.56 (3H, s), 3.55-3.47 (1H, m), 3.04-2.96 (2H, m), 2.88 (3H, s),2.15 (3H, s), 1.89-1.79 (2H, m).

Example 17(R)-5-(4-Cyano-phenyl)-2-(4-methanesulfonyl-benzyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 7 (65 mg, 0.14 mmol) was dissolved in DMF (3 mL) and cesiumcarbonate (91 mg, 0.28 mmol) and 4-methylsulfonylbenzyl bromide (50 mg,0.2 mmol) were added. The reaction mixture was stirred at RT for 3 hoursand then partitioned between EtOAc and water. The organic layer wasseparated, washed with brine, dried (Na₂SO₄) and evaporated in vacuo.The resulting residue was purified by silica gel chromatography elutingwith 80% EtOAc in cyclohexane to yield the title compound as a whitesolid (73 mg).

LC-MS (Method 3): Rt=4.78 min, m/z=624 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.11 (1H, s), 7.93-7.85 (4H, m), 7.84-7.77 (3H,m), 7.71 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=8.5 Hz), 6.00 (1H, s), 4.82(2H, dd, J=16.5 Hz and 36.5 Hz), 3.56 (3H, s), 3.17 (3H, s), 2.14 (3H,s).

Example 18(R)-5-(4-Cyano-phenyl)-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 18 (85 mg) was prepared from Example 7 (91 mg, 0.25 mmol) andIntermediate 14 (50 mg, 0.25 mmol) according to an analogous procedureto that described for Example 17.

LC-MS (Method 3): Rt=4.48 min, m/z=576 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.12 (1H, s), 7.92 (2H, dd, J=1 Hz and 7.5 Hz),7.87-7.79 (3H, m), 7.69 (2H, d, J=7.5 Hz), 5.96 (1H, s), 3.68-3.60 (1H,m), 3.56 (3H, s), 3.55-3.47 (1H, m), 3.04-2.96 (2H, m), 2.88 (3H, s),2.15 (3H, s), 1.89-1.79 (2H, m).

Example 195-(4-Cyano-phenyl)-2-(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-benzenesulfonyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (68 mg, 0.15 mmol) was dissolved in THF (2 mL), and cesiumcarbonate (81 mg, 0.25 mmol) and 4-(bromomethyl)-benzenesulfonylchloride (49 mg, 0.18 mmol) were added. The reaction mixture was stirredat RT for 1 hour and then evaporated in vacuo. The resulting residue wasre-dissolved in DMF (1 mL) and stirred at RT for a further 2 hours.N,N,N′-Trimethylethylenediamine (64 μL, 0.5 mmol) was added, andstirring at RT was continued for 5 hours. AdditionalN,N,N′-trimethylethylenediamine (150 μL, 1.2 mmol) was added, andstirring at RT was continued for 16 hours. The reaction mixture waspartitioned between EtOAc and water. The organic layer was separated,washed with brine, dried (Na₂SO₄) and evaporated in vacuo. The resultingresidue was purified by silica gel chromatography eluting with 10% MeOH,and the resulting residue was subjected to reverse phase HPLC using agradient of 40-60% acetonitrile in water with 0.1% ammonia and gave thetitle compound as a white solid (7 mg).

LC-MS (Method 3): Rt=3.84 min, m/z=710 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.03 (1H, s), 8.00-7.96 (1H, m), 7.89-7.85 (2H,m), 7.78 (2H, d, J=8 Hz), 7.59 (2H, d, J=8 Hz), 7.56 (2H, d, J=8 Hz),7.47 (2H, d, J=8 Hz), 5.87 (1H, s), 3.58 (2H, s), 3.51 (3H, s),2.48-2.43 (2H, m), 2.40-2.35 (2H, m), 2.13 (3H, s), 2.12 (6H, s), 2.08(3H, s).

Example 20(R)-5-(4-Cyano-phenyl)-2-[2-(4-methanesulfonyl-phenyl)-ethyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 7 (54 mg, 0.12 mmol) was dissolved in DMF (3 mL), and cesiumcarbonate (59 mg, 0.18 mmol) and1-(2-bromoethyl)-4-(methylsulfonyl)benzene (39 mg, 0.15 mmol) wereadded. The reaction mixture was stirred at RT for 16 hours, then thetemperature was raised to 70° C., and stirring was continued for 3hours. The reaction mixture was allowed to cool to RT, then furthercesium carbonate (59 mg, 0.18 mmol) and1-(2-bromoethyl)-4-(methylsulfonyl)benzene (39 mg, 0.15 mmol) wereadded. The reaction mixture was stirred at RT for 2 hours and thenpartitioned between EtOAc and water. The organic layer was separated,washed with brine, dried (Na₂SO₄) and evaporated in vacuo. The resultingresidue was purified by silica gel chromatography eluting with agradient of 50-80% EtOAc in cyclohexane to yield the title compound asan off-white solid (45 mg).

LC-MS (Method 3): Rt=4.81 min, m/z=638 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.12 (1H, s), 7.95-7.91 (1H, m), 7.90=7.80 (4H,m), 7.74 (2H, d, J=8 Hz), 7.63 (2H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz),5.90 (1H, s), 3.81-3.66 (2H, m), 3.54 (3H, s), 3.15 (3H, s) 2.87-2.82(2H, m), 2.14 (3H, s).

Example 215-(4-Cyano-phenyl)-2-(4-dimethylaminomethyl-benzyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 15 (105 mg, 0.16 mmol) was dissolved in THF (3 ml), andthen dimethylamine (2 M in THF, 400 μl, 0.8 mmol) was added. Thereaction mixture was stirred at RT for 16 hours and then filtered. Thefiltrate was collected and concentrated in vacuo. The resulting residuewas purified by silica gel chromatography eluting with a gradient of5-8% MeOH in DCM and gave the title compound as a white solid (72 mg).

LC-MS (Method 3): Rt=3.69 min, m/z=603 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.04 (1H, s), 7.87-7.79 (4H, m), 7.76-7.71 (1H,m), 7.64 (2H, d, J=8 Hz), 7.10 (2H, d, J=8 Hz), 6.95 (2H, d, J=8 Hz),5.95 (1H, s), 4.64 (1H, d, J=15 Hz), 4.56 (1H, d, J=15 Hz), 3.50 (3H,s), 3.28-3.21 (2H, m), 2.09 (3H, s), 2.05 (6H, s).

Example 22{4-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-ylmethyl]-benzyl}-trimethyl-ammoniumbromide

Intermediate 15 (105 mg, 0.16 mmol) was dissolved in a solution of 31%trimethylamine in ethanol. The reaction mixture was stirred at RT for 16hours and then filtered. The solid was collected by filtration and driedin vacuo to yield the title compound as a white solid (62 mg).

LC-MS (Method 3): Rt=3.71 min, m/z=617 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.10 (1H, s), 7.94-7.85 (4H, m), 7.82-7.77 (1H,m), 7.72 (2H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz), 7.19 (2H, d, J=8 Hz),6.00 (1H, s), 4.80 (1H, d, J=16 Hz), 4.72 (1H, d, J=16 Hz), 4.47 (2H,s), 3.57 (3H, s), 2.98 (9H, s), 2.16 (3H, s).

Example 235-(4-Cyano-phenyl)-2-(5-methanesulfonyl-pyridin-2-ylmethyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (50 mg, 0.11 mmol) was dissolved in DMF (1 mL), and cesiumcarbonate (43 mg, 0.13 mmol), 2-chloromethyl-5-methanesulfonyl-pyridine(25 mg, 0.12 mmol), and sodium iodide (2 mg, 0.011 mmol) were added. Thereaction mixture was stirred at RT for 16 hours and then partitionedbetween EtOAc and water. The organic layer was separated, and theaqueous layer further extracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresulting residue was purified by silica gel chromatography eluting witha gradient of 0-50% EtOAc in DCM to yield the title compound as a whitesolid (41 mg).

LC-MS (Method 3): Rt=4.63 min, m/z=625 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.86 (1H, d, J=2 Hz), 8.18 (1H, dd, J=9 and 2Hz), 8.05 (1H, s), 7.86-7.82 (4H, m), 7.75-7.71 (1H, m), 7.67 (2H, d,J=9 Hz), 7.31 (1H, d, J=8 Hz), 5.97 (1H, s), 4.91 (1H, d, J=17 Hz), 4.83(1H, d, J=17 Hz), 3.52 (3H, s), 3.24 (3H, s), 2.10 (3H, s).

Example 245-(4-Cyano-phenyl)-7-methyl-3-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Example 1 (35 mg, 0.08 mmol) was dissolved in THF (2 mL), andN-(3-hydroxypropyl)-2-pyrrolidone (12 μL, 0.09 mmol) andtriphenylphosphine (59 mg, 0.22 mmol) were added followed by diethylazodicarboxylate (42 μl, 0.27 mmol). The reaction mixture was stirred atRT for 2 hours and was then partitioned between EtOAc and water. Theorganic layer was separated, and the aqueous layer further extractedwith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄) and evaporated in vacuo. The resulting residue was purified bysilica gel chromatography eluting with a gradient of 0-10% MeOH in DCM.Further purification was carried out by reverse phase HPLC using agradient of 50-98% MeOH in water+0.1% formic acid to yield the titlecompound as a white solid (10 mg).

LC-MS (Method 3): Rt=4.50 min, m/z=581 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.76 (1H, d, J=8 Hz), 7.70-7.63 (3H, m),7.59-7.53 (4H, m), 6.10 (1H, s), 3.61 (3H, s), 3.60-3.56 (1H, m),3.50-3.43 (1H, m), 3.25 (2H, t, J=7 Hz), 3.21-3.13 (2H, m), 2.29 (2H, t,J=8 Hz), 2.23 (3H, s), 1.97-1.91 (2H, m), 1.84-1.78 (2H, m).

Example 255-(4-Cyano-phenyl)-2-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 17 (48 mg, 0.09 mmol) was dissolved in DMF (1 mL), and thendiisopropylethylamine (48 μL, 0.28 mmol) and HATU (39 mg, 0.10 mmol)were added. The reaction mixture was stirred at RT for 30 minutes andthen N,N,N-trimethylethylenediamine (36 μL, 0.28 mmol) was added. After3 hours of stirring at RT, another portion of HATU was added (10 mg,0.03 mmol), and stirring was continued for 1 hour. The reaction mixturewas partitioned between EtOAc and water. The organic layer wasseparated, and the aqueous layer further extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄) andevaporated in vacuo. The resulting residue was purified by silica gelchromatography eluting with a gradient of 0-10% (2M NH₃ in MeOH) in DCMto give the title compound as a white solid (40 mg).

LC-MS (Method 3): Rt=3.52 min, m/z=598 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H, d, J=8 Hz), 7.66-7.62 (3H, m), 7.58(1H, s), 7.56-7.53 (3H, m), 6.15 (1H, s), 4.37 (1H, d, J=17 Hz), 4.28(1H, d, J=17 Hz), 3.63 (3H, s), 3.40 (1H, m), 3.22 (1H, t, J=7 Hz), 2.90(3H, s), 2.42-2.35 (2H, m), 2.22 (3H, s), 2.20 (3H, s), 2.16 (3H, s).

Example 265-(4-Cyano-phenyl)-2-{[(3-dimethylamino-propyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 17 (57 mg, 0.11 mmol) was dissolved in DMF (1 mL), and thendiisopropylethylamine (56 μL, 0.33 mmol) and HATU (63 mg, 0.17 mmol)were added. The reaction mixture was stirred at RT for 30 minutes, thenN,N,N-trimethylpropanediamine (49 μL, 0.33 mmol) was added, and stirringwas continued for a further 2 hours. The reaction mixture waspartitioned between EtOAc and water. The organic layer was separated,and the aqueous layer further extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo.The resulting residue was purified by silica gel chromatography elutingwith a gradient of 0-10% (2M NH₃ in MeOH) in DCM to yield the titlecompound as a white solid (42 mg).

LC-MS (Method 3): Rt=3.52 min, m/z=612 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.72 (1H, t, J=8 Hz), 7.66-7.61 (3H, m),7.59-7.50 (4H, m), 6.17 (1H, s), 4.55 (2H, s), 3.63 (3H, s), 3.30 (1H,t, J=8 Hz), 3.25-3.16 (1H, m), 2.82 (3H, s), 2.20 (3H, s), 2.16 (3H, s),2.14-2.10 (2H, m), 2.06 (3H, s), 1.66-1.59 (2H, m).

Example 27[2-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)-ethyl]-trimethyl-ammoniumbromide

Example 25 (28 mg, 0.05 mmol) was dissolved in acetonitrile (0.5 mL),and then methyl bromide (23 μL of 30% solution in acetonitrile, 0.07mmol) was added. The reaction mixture was stirred at RT for 5 days, andduring this period methyl bromide (50 μL) was added every 12 hours.Potassium carbonate (20 mg) was then added to the reaction mixture, andstirring was continued for 12 hours. The reaction mixture was filteredand the filtrate evaporated in vacuo to yield the title compound as awhite solid (32 mg).

LC-MS (Method 3): Rt=3.48 min, m/z=612 [M]⁺

¹H NMR (400 MHz, DMSO) δ 8.05 (1H, s), 7.90-7.74 (5H, m), 4.68 (2H, d,J=9 Hz), 5.93 (1H, s), 4.47 (1H, d, J=17 Hz), 4.41 (1H, d, J=17 Hz),3.59-3.53 (2H, m), 3.51 (3H, s), 3.31-3.23 (2H, m), 2.97 (9H, s), 2.88(3H, s), 2.10 (3H, s).

Example 28[3-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)propyl]-trimethyl-ammonium;bromide

Example 26 (32 mg, 0.05 mmol) was dissolved in acetonitrile (0.5 mL),and then methyl bromide (25 μL of 30% solution in acetonitrile, 0.07mmol) was added. The reaction mixture was stirred at RT for 3 days, andduring this period methyl bromide (25 μL) was added every 12 hours. Thereaction mixture was filtered, and the filtrate evaporated in vacuo toyield the title compound as a white solid (36 mg).

LC-MS (Method 3): Rt=3.51 min, m/z=626 [M]⁺

¹H NMR (400 MHz, DMSO) δ 8.05 (1H, s), 7.90-7.74 (5H, m), 7.64 (2H, d,J=8 Hz), 5.93 (1H, s), 4.41 (1H, d, J=17 Hz), 4.36 (1H, d, J=17 Hz),3.52 (3H, s), 3.21-3.06 (4H, m), 2.93 (9H, s), 2.84 (3H, s), 2.10 (3H,s), 1.80-1.73 (2H, m).

Example 295-(4-Cyano-phenyl)-2-{[(4-dimethylamino-butyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 17 (50 mg, 0.10 mmol) was dissolved in DMF (1 mL). anddiisopropylethylamine (50 μL, 0.29 mmol) and HATU (41 mg, 0.11 mmol)were added. The reaction mixture was stirred at RT for 30 minutes, thenN,N,N-trimethylbutanediamine (38 mg, 0.29 mmol) was added, and stirringwas continued for a further 18 hours. The reaction mixture waspartitioned between EtOAc and water. The organic layer was separated,and the aqueous layer further extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated in vacuo.The resulting residue was purified by silica gel chromatography elutingwith a gradient of 0-10% (2M NH₃ in MeOH) in DCM to yield the titlecompound as a white solid (34 mg).

LC-MS (Method 3): Rt=3.54 min, m/z=626 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H, t, J=8 Hz), 7.65-7.62 (3H, m),7.57-7.53 (4H, m), 6.15 (1H, s), 4.30 (1H, d, J=17 Hz), 4.26 (1H, d,J=17 Hz), 3.63 (3H, s), 3.29 (2H, t, J=7 Hz), 2.88 (3H, s), 2.25 (2H, t,J=8 Hz), 2.20 (3H, s), 2.18 (3H, s), 2.13 (3H, s), 1.55-1.36 (4H, m).

Example 305-(4-Cyano-phenyl)-2-{[(5-dimethylamino-pentyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 17 (45 mg, 0.09 mmol) was dissolved in DMF (1 mL), and thendiisopropylethylamine (75 μL, 0.44 mmol) and HATU (51 mg, 0.14 mmol)were added. The reaction mixture was stirred at RT for 30 minutes, thenN,N,N-trimethylpentanediamine (63 mg, 0.44 mmol) was added, and stirringwas continued for a further 18 hours. The reaction mixture waspartitioned between EtOAc and water. The organic layer was separated,and the aqueous layer extracted with EtOAc. The combined organic layerswere washed with brine, dried (Na₂SO₄) and evaporated in vacuo. Theresulting residue was purified by silica gel chromatography eluting witha gradient of 0-10% (2M NH₃ in MeOH) in DCM to give the title compoundas a white solid (44 mg).

LC-MS (Method 3): Rt=3.59 min, m/z=640 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H, t, J=8 Hz), 7.67-7.64 (3H, m),7.57-7.52 (4H, m), 6.12 (1H, s), 4.37 (2H, s), 3.64 (3H, s), 3.45 (2H,dd, J=14, 7 Hz), 2.86 (3H, s), 2.64 (6H, s), 2.43 (2H, br s), 2.20 (3H,s), 1.65-1.21 (6H, m).

Example 31[4-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)-butyl]-trimethylammoniumbromide

Example 29 (21 mg, 0.03 mmol) was dissolved in a 30% methyl bromide inacetonitrile solution (1 mL), and potassium carbonate (30 mg) was added.The reaction mixture was stirred at RT for 3 days and then filtered andthe filtrate evaporated in vacuo to yield the title compound as a whitesolid (25 mg).

LC-MS (Method 3): Rt=3.54 min, m/z=640 [M]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.76-7.74 (2H, m), 7.70-7.66 (2H, m),7.57-7.54 (4H, m), 6.09 (1H, s), 4.40 (1H, d, J=17 Hz), 4.35 (1H, d,J=17 Hz), 3.65 (3H, s), 3.65-3.60 (2H, m), 3.36-3.29 (2H, m), 3.16 (9H,s), 2.90 (3H, s), 2.20 (3H, s), 1.71-1.59 (4H, m).

Example 32[5-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)pentyl]-trimethyl-ammonium;bromide

Example 30 (34 mg, 0.05 mmol) was dissolved in a 30% methyl bromide inacetonitrile solution (1 mL), and then potassium carbonate (30 mg) wasadded. The reaction mixture was stirred at RT for 24 hours and thenfiltered and evaporated in vacuo to yield the title compound as a whitesolid (37 mg).

LC-MS (Method 3): Rt=3.62 min, m/z=654 [M]⁺

¹H NMR (400 MHz, DMSO) δ 8.04 (1H, s), 7.88-7.75 (5H, m), 7.64 (2H, dd,J=8, 1 Hz), 5.92 (1H, s), 4.38 (2H, s), 3.52 (3H, s), 3.26 (9H, s),3.17-3.13 (4H, m), 2.94 (3H, s), 2.10 (3H, s), 1.64-1.54 (2H, m),1.46-1.34 (2H, m), 1.19-1.07 (2H, m).

Example 33(R)-5-(4-Cyano-phenyl)-2-{[(5-dimethylamino-pentyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]-triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester

Intermediate 26 (250 mg, 0.46 mmol) was dissolved in DMF (5 mL), andthen diisopropylethylamine (240 μL, 1.4 mmol) and HATU (266 mg, 0.7mmol) were added. The reaction mixture was stirred at RT for 40 minutes,then N,N,N-trimethylpentanediamine (288 mg, 2.0 mmol) in DMF (1 mL) wasadded, and stirring was continued for a further 18 hours. The reactionmixture was partitioned between EtOAc and water. The organic layer wasseparated, and the aqueous layer extracted with EtOAc. The combinedorganic layers were washed with brine, dried (Na₂SO₄) and evaporated invacuo. The resulting residue was purified by silica gel chromatographyeluting with a gradient of 4-8% (2 M NH₃ in MeOH) in DCM followed by agradient of 6-7% (2 M NH₃ in MeOH) in DCM. The resulting residue waspurified by MDAP to yield the title compound as an off-white solid (88mg).

LC-MS (Method 3): Rt=3.52 min, m/z=640 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ 7.73 (1H, t, J=8 Hz), 7.67-7.64 (3H, m),7.57-7.52 (4H, m), 6.12 (1H, s), 4.37 (2H, s), 3.64 (3H, s), 3.45 (2H,dd, J=14, 7 Hz), 2.86 (3H, s), 2.64 (6H, s), 2.43 (2H, br s), 2.20 (3H,s), 1.65-1.21 (6H, m).

Example 34(R)-[5-({2-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)pentyl]-trimethyl-ammoniumchloride

Example 33 (88 mg, 0.14 mmol) was dissolved in a 30% methyl bromide inacetonitrile solution (2 mL), and then potassium carbonate (39 mg) wasadded. The reaction mixture was stirred at RT for 24 hours and thenfiltered and evaporated in vacuo and dissolved in water. The resultingsolution was eluted through Amberlite IRA458 resin and freeze dried togive the title compound as a white solid (49 mg).

LC-MS (Method 3): Rt=3.62 min, m/z=654 [M]⁺

¹H NMR (400 MHz, DMSO) δ 8.04 (1H, s), 7.88-7.75 (5H, m), 7.64 (2H, dd,J=8, 1 Hz), 5.92 (1H, s), 4.38 (2H, s), 3.52 (3H, s), 3.26 (9H, s),3.17-3.13 (4H, m), 2.94 (3H, s), 2.10 (3H, s), 1.64-1.54 (2H, m),1.46-1.34 (2H, m), 1.19-1.07 (2H, m).

Example 352-[3-(Acetyl-methyl-amino)-propyl]-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacidmethyl ester

To a solution of Intermediate 18 (0.12 g, 0.19 mmol) in DCM (2.5 mL),was added TFA (0.25 mL). The resulting mixture was stirred at RT for 1hour, and then evaporated in vacuo. The resulting residue was taken upin DCM (4 mL), and triethylamine (86 μL, 0.62 mmol) was added, followedby acetic anhydride (47 μL, 0.50 mmol). The reaction mixture was stirredat RT for 30 mins and was then partitioned between EtOAc and water. Theorganic layer was separated, and the aqueous layer further extractedwith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄) and evaporated in vacuo. The resulting residue was purified bysilica gel chromatography eluting with a gradient 0-10% MeOH in DCM toyield the title compound as a white solid (80 mg).

LC-MS (Method 3): Rt=4.45 min, m/z=569 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.06 (1H, d, J=6 Hz), 7.87-7.85 (2H, m),7.82-7.75 (3H, m), 7.63 (2H, dd, J=8, 2 Hz), 5.91 (1H, s), 3.50 (3H, s),3.46-3.30 (2H, m), 3.10-2.99 (2H, m), 2.75 (3H, s), 2.10 (3H, s), 1.84(3H, s), 1.58-1.50 (2H, m).

Example 365-(4-Cyano-phenyl)-2-[3-(methanesulfonyl-methyl-amino)-propyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacidmethyl ester

To a solution of Intermediate 18 (0.12 g, 0.19 mmol) in DCM (2.5 mL) andTFA (0.25 mL) was added. The resulting mixture was stirred at RT for 1hour and then evaporated in vacuo. The resulting residue was taken up inDCM (4 mL), and then triethylamine (105 μL, 0.75 mmol) added, followedby methanesulfonyl chloride (28 μL, 0.36 mmol). The reaction mixture wasstirred at RT for 30 mins and then partitioned between EtOAc and water.The organic layer was separated, and the aqueous layer further extractedwith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄) and evaporated in vacuo. The resulting residue was purified bysilica gel chromatography eluting with a gradient of 0-10% MeOH in DCMas eluent to yield the title compound as a white solid (106 mg).

LC-MS (Method 3): Rt=4.45 min, m/z=605 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.06 (1H, s), 7.88-7.85 (2H, m), 7.81-7.75 (3H,m), 7.63 (2H, d, J=8 Hz), 5.91 (1H, s), 3.51 (3H, s), 3.41-3.31 (2H, m),2.87 (2H, td, J=8, 2 Hz), 2.72 (3H, s), 2.56 (3H, s), 2.10 (3H, s),1.69-1.58 (2H, m).

Example 37(3-{3-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumtoluene-4-sulfonate

Intermediate 23 (68 mg, 0.09 mmol) was dissolved in 31% trimethylaminein ethanol (3 ml) and stirred at RT for 16 hours. The solvent wasevaporated in vacuo, and the resulting residue repeatedly azeotropedwith diethyl ether until a solid formed. The solid was collected anddried in vacuo to yield the title compound as an off-white solid (51mg).

LC-MS (Method 3): Rt=3.59 min, m/z=661 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ 8.12 (1H, s), 7.94-7.89 (2H, m), 7.88-7.80 (3H,m), 7.69 (2H, d, J=8 Hz), 7.47 (2H, d, J=8 Hz), 7.11 (2H, d, J=8 Hz),5.96 (1H, s), 3.68-3.60 (1H, m), 3.59-3.50 (1H, m), 3.56 (3H, s),3.38-3.32 (2H, m), 3.13-3.07 (4H, m), 3.05 (9H, s), 2.29 (3H, s), 2.15(3H, s), 2.12-2.04 (2H, m), 1.90-1.79 (2H, m).

Example 38(R)-(3-{3-[5-(4-Cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumchloride

Intermediate 29 (128 mg, 0.17 mmol) was dissolved in 31% trimethylaminein ethanol (6 ml) and stirred at RT for 16 hours. The solvent wasremoved, and the resulting residue was purified by reverse phase HPLCusing a gradient of 10-98% acetonitrile in water with 0.1% formic acid.The title compound was obtained following elution through AmberliteIRA458 resin and freeze-drying of the eluent to give a white solid (72mg).

LC-MS (Method 3): Rt=3.52 min, m/z=661 [M]⁺

¹H NMR (400 MHz, DMSO) δ 8.12 (1H, s), 7.94-7.89 (2H, m), 7.88-7.80 (3H,m), 7.69 (2H, d, J=8 Hz), 5.96 (1H, s), 3.68-3.60 (1H, m), 3.59-3.50(1H, m), 3.56 (3H, s), 3.38-3.32 (2H, m), 3.13-3.07 (4H, m), 3.05 (9H,s), 2.15 (3H, s), 2.12-2.04 (2H, m), 1.90-1.79 (2H, m).

Example 39(3-{3-[6-Cyano-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumtoluene-4-sulfonate

Example 39 (89 mg) was prepared from Example 14 (331 mg, 0.78 mmol) andIntermediate 20 (296 mg, 1 mmol) according to analogous procedures tothose described for Intermediate 23 then Example 37.

LC-MS (Method 3): Rt=3.45 min, m/z=628 [M]⁺

¹H NMR (400 MHz, DMSO) δ 8.12 (1H, s), 7.93-7.84 (4H, m), 7.81-7.70 (3H,m), 7.43 (2H, d, J=7.6 Hz), 7.06 (2H, d, J=7.6 Hz), 5.88 (1H, s),3.65-3.48 (2H, m), 3.33-3.2 (2H, m), 3.10-3.04 (4H, m), 3.01 (9H, s),2.24 (3H, s), 2.10-1.98 (2H, m), 1.89 (3H, s), 1.86-1.77 (2H, m).

Biological Assay.

Compounds of this invention were tested for potency in a humanneutrophil elastase (HNE) enzyme activity assay.

HNE Enzyme Assay.

Assays were performed in 96-well plates in a total assay volume of 100μl. The final concentration of elastase enzyme (human leukocyteelastase, Sigma E8140) was 0.0036 units/well or 0.00072 U/mL. Thepeptide substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem #324740) wasused at a final concentration of 100 μM. The final concentration of DMSOwas 1% in the assay buffer (0.05M Tris.HCl, 0.1M NaCl, 0.1M CaCl₂,0.0005% brij-35, pH 7.5). The enzymatic reaction was started by additionof the enzyme and incubated at 25° C. for 30 minutes. After incubation,the reaction was stopped by addition of soybean trypsin inhibitor (SigmaT9003) at a final concentration of 50 μg/well. Fluorescence was measuredusing a Molecular Devices fluorescence plate reader using 380 nmexcitation and 460 nm emission wavelengths.

A dose response to each compound was performed, and the effect of thecompound in each experiment was expressed as a percentage inhibition ofthe control enzyme fluorescence. Dose response curves were plotted andcompound potency (IC₅₀) was determined. Compounds were tested in atleast two separate experiments.

IC₅₀s for tested Examples, representative of the invention, are shown inthe following table:

Example HNE inhibition 33, 34, 38, 18, 13, 39, 14, 37, 36, 35, 32, 30,31, 29, 21, 22, 11, 27, 28, 16, 26, 25, 24, 15, 10, 23, 8, 20, ++++ 17,9, 3, 2, 1, 5, 6 19, 12, 4 +++ In the table above, HNE enzyme inhibition(IC₅₀ values) are indicated as follows: >500 nM “+”; 100 to 500 nM “++”;20 to 100 nM “+++”; and <20 nM “++++”.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A compound represented by formula (I):

wherein: A is CH or N; R₁ is: hydrogen; (C₁-C₆)alkyl; NR₇R₈(C₁-C₆)alkyl;(C₁-C₄)alkenyl; phenyl(C₁-C₆)alkyl wherein such phenyl ring isoptionally substituted by NR₁₅R₁₆(C₁-C₆)alkyl or byN⁺R₁₅R₁₆R₁₇(C₁-C₆)alkyl; a group —CH₂(CH₂)_(n)OH; a group—(CH₂)_(n)CONR₅R₆; a group —(CH₂)_(n)SO₂NR₅R₆; a group—CH₂—(CH₂)_(n)NR₅SO₂R₆; a group —(CH₂)_(t)—(C₆H₄)—SO₂(C₁-C₄)alkyl; agroup —(CH₂)_(n)SO₂(C₁-C₄)alkyl wherein such (C₁-C₄)alkyl is optionallysubstituted by a group —NR₁₅R₁₆ or —N⁺R₁₅R₁₆R₁₇; a group —SO₂-phenylwherein such phenyl ring is optionally substituted by NR₇R₈(C₁-C₆)alkyl;and a group —(CH₂)_(n)—W wherein W is a 5 or 6-membered heteroaryl ringwhich is optionally substituted by a group —SO₂(C₁-C₄)alkyl; n is 1, 2or 3; t is zero, 1, 2 or 3; r is zero, 1, 2, 3 or 4; R₅ is hydrogen,(C₁-C₆)alkyl, NR₁₆R₁₅(C₁-C₆)alkyl, or N⁺R₁₇R₁₅R₁₆(C₁-C₆)alkyl; R₆ ishydrogen or (C₁-C₆)alkyl; R₇ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, —SO₂(C₁-C₄)alkyl, or NR₁₆R₁₅(C₁-C₆)alkyl; R₈ ishydrogen or (C₁-C₆)alkyl; or, alternatively, R₇ and R₈, together withthe nitrogen atom to which they are attached, form a(C₅-C₇)heterocycloalkyl ring system which is optionally substituted byone or more groups (C₁-C₆)alkyl and oxo; R₁₆ is hydrogen or(C₁-C₆)alkyl; R₁₅ is hydrogen or (C₁-C₆)alkyl; R₁₇ is hydrogen or(C₁-C₆)alkyl; R₂ is hydrogen or —SO₂R₄, wherein R₄ is optionallysubstituted (C₁-C₆)alkyl, hydroxyl(C₁-C₆)alkyl, amino, mono- ordi(C₁-C₄)alkylamino, wherein (C₁-C₄)alkyl may be optionally substituted,optionally substituted (C₃-C₆)-cycloalkyl, halogen, or optionallysubstituted phenyl; R₁₄ is a group cyano or a group —C(O)—XR₃; X is —O—,—(CH₂)—, or —NH—; R₃ is: hydrogen; (C₁-C₆)alkyl; a group of formula-[Alk¹]-Z, wherein Alk¹ is a (C₁-C₄)alkylene radical and Z is: (i)—NR₉R₁₀, wherein R₉ and R₁₀ are independently hydrogen, optionallysubstituted (C₁-C₆)alkyl or an optionally substituted (C₃-C₆)cycloalkylgroup, or, taken together with the nitrogen to which they are attached,form an optionally substituted monocyclic (C₅-C₇)heterocyclic ring whichmay contain a further heteroatom selected from the group consisting ofN, O, and S; or (ii) —N⁺R₁₁R₁₂R₁₃, wherein R₁₁, R₁₂ and R₁₃ are eachindependently optionally substituted (C₁-C₆)alkyl or optionallysubstituted (C₃-C₆)cycloalkyl group; or any two of R₁₁, R₁₂ and R₁₃,taken together with the nitrogen to which they are attached, form anoptionally substituted monocyclic (C₅-C₇)heterocyclic ring which maycontain a further heteroatom selected from the group consisting of N, O,and S and the other of R₁₁, R₁₂ and R₁₃ is an optionally substituted(C₁-C₆)alkyl or an optionally substituted (C₃-C₆)cycloalkyl group; or aradical of formula —(CH₂)_(q)-[Q]-(CH₂)_(p) Z wherein Z is as abovedefined, q is an integer ranging from zero to 3, p is an integer rangingfrom zero to 3 and Q represents a divalent group selected from the groupconsisting of —O—, optionally substituted phenylene, optionallysubstituted (C₅-C₇)heterocycloalkylene, optionally substituted(C₃-C₆)cycloalkyl, and optionally substituted pyridinylene; wherein ifone or more groups —(C₁-C₆)alkylN⁺R₁₁R₁₂R₁₃ or —(C₁-C₆)alkylN⁺R₁₅R₁₆R₁₇are present, they form quaternary salts with a pharmaceuticallyacceptable counter ion; and wherein groups R₅, R₆, R₇, R₈, R₁₅, R₁₆,R₁₇, and n may assume the same or different meanings at each occurrence,if present in more than one group; with the proviso that the compound offormula (I) is not:5-(4-cyanophenyl)-2-(2-dimethylaminoethyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid 2-dimethylaminoethyl ester;{2-[5-(4-cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonyloxy]ethyl}-trimethylammonium;or5-(4-cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid; or a pharmaceutically acceptable salt thereof or an N-oxidethereof.
 2. A compound, pharmaceutically acceptable salt thereof, orN-oxide thereof according to claim 1, wherein A is a group CH.
 3. Acompound, pharmaceutically acceptable salt thereof, or N-oxide thereofaccording to claim 1, wherein R₂ is hydrogen or a —SO₂R₄, wherein R₄ is(C₁-C₆)alkyl.
 4. A compound, pharmaceutically acceptable salt thereof,or N-oxide thereof according to claim 1, wherein R₁₄ is a group—C(O)—XR₃.
 5. A compound, pharmaceutically acceptable salt thereof, orN-oxide thereof according to claim 1, wherein X is —O— or —NH—.
 6. Acompound, pharmaceutically acceptable salt thereof, or N-oxide thereofaccording to claim 1, wherein R₃ is: hydrogen; (C₁-C₆)alkyl; or aradical of formula -[Alk¹]-Z, wherein Alk¹ represents a (C₁-C₄)alkyleneradical, and Z is: (i) —NR₉R₁₀, wherein R₉ and R₁₀ are independentlyhydrogen or optionally substituted (C₁-C₆)alkyl; or (ii) —N⁺R₁₁R₁₂R₁₃,wherein R₁₁, R₁₂ and R₁₃ are each independently optionally substituted(C₁-C₆)alkyl.
 7. A compound, pharmaceutically acceptable salt thereof,or N-oxide thereof according to claim 1, wherein R₁ is hydrogen,(C₁-C₆)alkyl, NR₇R₈(C₁-C₆)alkyl, (C₁-C₄)alkenyl, phenyl(C₁-C₆)alkyl,wherein such phenyl ring is optionally substituted by a group—(C₁-C₆)alkylNR₁₅R₁₆ or by a group —(C₁-C₆)alkylN⁺R₁₅R₁₆R₁₇,—(CH₂)_(n)CONR₅R₆, —CH₂—(CH₂)_(n)NR₅SO₂R₆,—(CH₂)_(t)—(C₆H₄)—SO₂(C₁-C₄)alkyl, —(CH₂)_(r)SO₂(C₁-C₄)alkyl, whereinsuch (C₁-C₄)alkyl is optionally substituted by a group —NR₁₅R₁₆ or—N⁺R₁₅R₁₆R₁₇, —SO₂-phenyl, wherein such phenyl ring is optionallysubstituted by a group —(C₁-C₆)alkylNR₇R₈, and —(CH₂)_(n)W, wherein W isa 5 or 6-membered heteroaryl ring, which is optionally substituted by agroup —SO₂(C₁-C₄)alkyl.
 8. A compound, pharmaceutically acceptable saltthereof, or N-oxide thereof according to claim 1, which is a compoundselected in the group consisting of:5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;2-carbamoylmethyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyanophenyl)-2-(2-dimethylamino-propyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;2-benzyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;2-allyl-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyanophenyl)-2,7-dimethyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;(R)-5-(4-cyanophenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid;5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid 2-dimethylamino-ethyl ester;5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid 3-dimethylamino-propyl ester;5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid ethylamide;5-(4-cyano-2-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-2-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile;5-(4-cyano-phenyl)-2-(4-methanesulfonyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;(R)-5-(4-cyano-phenyl)-2-(4-methanesulfonyl-benzyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;(R)-5-(4-cyano-phenyl)-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-(4-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-benzenesulfonyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;(R)-5-(4-cyano-phenyl)-2-[2-(4-methanesulfonyl-phenyl)-ethyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-(4-dimethylaminomethyl-benzyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;{4-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-ylmethyl]-benzyl}-trimethyl-ammoniumbromide;5-(4-cyano-phenyl)-2-(5-methanesulfonyl-pyridin-2-ylmethyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-7-methyl-3-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-{[(2-dimethylamino-ethyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-{[(3-dimethylamino-propyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;[2-({2-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)-ethyl]-trimethyl-ammoniumbromide;[3-({2-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)propyl]-trimethyl-ammoniumbromide;5-(4-cyano-phenyl)-2-{[(4-dimethylamino-butyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-{[(5-dimethylamino-pentyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;[4-({2-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)-butyl]-trimethylammoniumbromide;[5-({2-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)pentyl]-trimethyl-ammoniumbromide;(R)-[5-({2-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-acetyl}-methyl-amino)pentyl]-trimethyl-ammoniumchloride;2-[3-(acetyl-methyl-amino)-propyl]-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethylphenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;5-(4-cyano-phenyl)-2-[3-(methanesulfonyl-methyl-amino)-propyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester;(3-{3-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumtoluene-4-sulfonate;(R)-(3-{3-[5-(4-cyano-phenyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumchloride;5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitrile;(3-{3-[6-cyano-5-(4-cyano-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-5,8-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-2-yl]-propane-1-sulfonyl}-propyl)-trimethylammoniumtoluene-4-sulfonate; and(R)-5-(4-cyano-phenyl)-2-{[(5-dimethylamino-pentyl)-methyl-carbamoyl]-methyl}-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylicacid methyl ester; or a pharmaceutically acceptable salt of saidcompound or an N-oxide of said compound.
 9. A compound, pharmaceuticallyacceptable salt thereof, or N-oxide thereof according to claim 1, whichis a compound represented by formula (I)′ wherein the absoluteconfiguration of carbon (1) is that shown below:


10. A compound, pharmaceutically acceptable salt thereof, or N-oxidethereof according to claim 1, which is a pharmaceutically acceptablesalt.
 11. A pharmaceutical composition, comprising a compound,pharmaceutically acceptable salt thereof, or N-oxide thereof accordingto claim 1 and a pharmaceutically acceptable carrier or excipient.
 12. Apharmaceutical composition according to claim 11, which is in a formsuitable for oral administration or administration by the pulmonaryroute.
 13. A method for the treatment of a disease or condition in whichHNE is implicated, comprising administering to an effective amount of acompound, pharmaceutically acceptable salt thereof, or N-oxide thereofaccording to claim 1 to a subject in need thereof.
 14. A methodaccording to claim 13, wherein said disease or condition is chronicobstructive pulmonary disease, bronchiectasis, chronic bronchitis, lungfibrosis, pneumonia, acute respiratory distress syndrome, pulmonaryemphysema, smoking-induced emphysema, or cystic fibrosis.
 15. A methodaccording to claim 13, wherein said disease or condition is asthma,rhinitis, psoriasis, atopic dermatitis, non-atopic dermatitis, Crohn'sdisease, ulcerative colitis, or irritable bowel disease.